Inhibiting agents for Bruton&#39;s tyrosine kinase

ABSTRACT

Provided are compounds of Formula (I), or pharmaceutically acceptable salts thereof, and methods for their use and production.

RELATED APPLICATIONS

This application is a continuation application of U.S. Application Ser.No. 15/952,505, filed on Apr. 13, 2018, which claims the benefit of thefiling date, under 35 U.S.C. § 119(e), of U.S. Provisional ApplicationNo. 62/485,745, filed on Apr. 14, 2017. The entire contents of each ofthe above-referenced applications are incorporated herein by reference.

TECHNICAL FIELD

Provided are certain agents that inhibit Bruton's tyrosine kinase (Btk),and methods of making and using such agents.

BACKGROUND

Protein kinases are a large multigene family consisting of more than 500proteins which play a critical role in the development and treatment ofa number of human diseases in oncology, neurology and immunology. TheTec kinases are non-receptor tyrosine kinases which consists of fivemembers (Tec (tyrosine kinase expressed in hepatocellular carcinoma),Btk (Bruton's tyrosine kinase), Itk (interleukin-2 (IL-2)-inducibleT-cell kinase; also known as Emt or Tsk), Rlk (resting lymphocytekinase; also known as Txk) and Bmx (bone-marrow tyrosine kinase gene onchromosome X; also known as Etk)) and are primarily expressed inhaematopoietic cells, although expression of Bmx and Tec has beendetected in endothelial and liver cells. Tec kinases (Itk, Rlk and Tec)are expressed in T cell and are all activated downstream of the T-cellreceptor (TCR). Btk is a downstream mediator of B cell receptor (BCR)signaling which is involved in regulating B cell activation,proliferation, and differentiation. More specifically, Btk contains a PHdomain that binds phosphatidylinositol (3,4,5)-trisphosphate (PIP3).PIP3 binding induces Btk to phosphorylate phospholipase C (PLCy), whichin turn hydrolyzes PIP2 to produce two secondary messengers, inositoltriphosphate (IP3) and diacylglycerol (DAG), which activate proteinkinase PKC, which then induces additional B-cell signaling. Mutationsthat disable Btk enzymatic activity result in XLA syndrome (X-linkedagammaglobulinemia), a primary immunodeficiency. Given the criticalroles which Tec kinases play in both B-cell and T-cell signaling, Teckinases are targets of interest for autoimmune disorders.

Consequently, there is a great need in the art for effective inhibitorsof Btk.

SUMMARY

A first embodiment of the invention is a compound of Formula (I):

or a pharmaceutically acceptable salt, wherein:

Ring A is 5-membered monocyclic heteroaryl containing 3 heteroatomsindependently selected from N, O and S, wherein said 5-memberedmonocyclic heteroaryl is optionally substituted with one or more R¹;

Q¹, Q², and Q³ are each, independently, selected from O, N(R²), andCH—R³, wherein at least two of Q¹, Q², and Q³ are C—R³;

W is selected from CH and N;

Y is selected from CH and N;

R¹ in each occurrence is independently selected from C₁₋₆alkyl and 3- to5-membered carbocyclyl, wherein said C₁₋₆alkyl and 3- to 5-memberedcarbocyclyl are optionally substituted with one or more R¹⁰;

R¹⁰ in each occurrence is independently selected from halo, —CN,C₁₋₆alkyl, and 3- to 5-membered carbocyclyl;

R² is selected from H, C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, 4- to6-membered monocyclic carbocyclyl, 4- to 6-membered monocyclicheterocyclyl, —CN, —C(O)R^(2a), —C(O)₂R^(2a), —C(O)N(R^(2a))₂,—S(O)₂R^(2a), and —S(O)₂N(R^(2a))₂, wherein said C₁₋₆alkyl, C₂₋₆alkenyl,C₂₋₆alkynyl, 4- to 6-membered monocyclic carbocyclyl, and 4- to6-membered monocyclic heterocyclyl are optionally substituted with oneor more R²⁰;

R^(2a) in each occurrence is independently selected from H, C₁₋₆alkyl,C₂₋₆alkenyl, C₂₋₆alkynyl, 4- to 6-membered monocyclic carbocyclyl, and4- to 6-membered monocyclic heterocyclyl, wherein said C₁₋₆alkyl,C₂₋₆alkenyl, C₂₋₆alkynyl, 4- to 6-membered monocyclic carbocyclyl, and4- to 6-membered monocyclic heterocyclyl in each occurrence areoptionally and independently substituted with one or more R²⁰;

R²⁰ in each occurrence is independently selected from C₁₋₆alkyl,C₂₋₆alkenyl, C₂₋₆alkynyl, 4- to 6-membered monocyclic carbocyclyl, 4- to6-membered monocyclic heterocyclyl, halo, —CN, —C(O)R^(20a),—C(O)₂R^(20a), —C(O)N(R^(20a))₂, —N(R^(20a))₂, —N(R^(20a))C(O)R^(20a),—N(R^(20a))C(O)₂R^(20a), —N(R^(20a))C(O)N(R^(20a))₂,—N(R^(20a))S(O)₂R^(20a), —OR^(20a), —OC(O)R^(20a), —OC(O)N(R^(20a))₂,—SR^(20a), —S(O)R^(20a), —S(O)₂R^(20a), —S(O)N(R^(20a))₂, and—S(O)₂N(R^(20a))₂;

R^(20a) in each occurrence is independently selected from H, C₁₋₆alkyl,C₂₋₆alkenyl, C₂₋₆alkynyl, 4- to 6-membered monocyclic carbocyclyl, and4- to 6-membered monocyclic heterocyclyl;

R³ is selected from H, C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, 4- to6-membered monocyclic carbocyclyl, 4- to 6-membered monocyclicheterocyclyl, halo, —CN, —C(O)R^(3a), —C(O)₂R^(3a), —C(O)N(R^(3a))₂,—N(R^(3a))₂, —N(R^(3a))C(O)R^(3a), —N(R^(3a))C(O)₂R^(3a),—N(R^(3a))C(O)N(R^(3a))₂, —N(R^(3a))S(O)₂R^(3a), —OR^(3a), —OC(O)R^(3a),—OC(O)N(R^(3a))₂, —SR^(3a), —S(O)R^(3a), —S(O)₂R^(3a), —S(O)N(R^(3a))₂,and —S(O)₂N(R^(3a))₂, wherein said C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl,4- to 6-membered monocyclic carbocyclyl, and 4- to 6-membered monocyclicheterocyclyl are optionally substituted with one or more R³⁰;

R^(3a) in each occurrence is independently selected from H, C₁₋₆alkyl,C₂₋₆alkenyl, C₂₋₆alkynyl, 4- to 6-membered monocyclic carbocyclyl, and4- to 6-membered monocyclic heterocyclyl, wherein said C₁₋₆alkyl,C₂₋₆alkenyl, C₂₋₆alkynyl, 4- to 6-membered monocyclic carbocyclyl, and4- to 6-membered monocyclic heterocyclyl in each occurrence areoptionally and independently substituted with one or more R³⁰;

R³⁰ in each occurrence is independently selected from C₁₋₆alkyl,C₂₋₆alkenyl, C₂₋₆alkynyl, 4- to 6-membered monocyclic carbocyclyl, 4- to6-membered monocyclic heterocyclyl, halo, —CN, —C(O)R^(30a),—C(O)₂R^(30a), —C(O)N(R^(30a))₂, —N(R^(30a))₂, —N(R^(30a))C(O)R^(30a),—N(R^(30a))C(O)₂R^(30a), —N(R^(30a))C(O)N(R^(30a))₂,—N(R^(30a))S(O)₂R^(3a), —OR^(30a), —OC(O)R^(30a), —OC(O)N(R^(30a))₂,—SR^(30a), —S(O)R^(30a), —S(O)₂R^(30a), —S(O)N(R^(30a))₂, and—S(O)₂N(R^(30a))₂;

R^(30a) in each occurrence is independently selected from H, C₁₋₆alkyl,C₂₋₆alkenyl, C₂₋₆alkynyl, 4- to 6-membered monocyclic carbocyclyl, and4- to 6-membered monocyclic heterocyclyl;

R⁴ is selected from H and C₁₋₆alkyl, wherein said C₁₋₆alkyl isoptionally substituted with one or more halo;

R⁵ is selected from H and C₁₋₆alkyl wherein said C₁₋₆alkyl is optionallysubstituted with one or more halo;

R⁶ is selected from H and C₁₋₆alkyl, wherein said C₁₋₆alkyl isoptionally substituted with one or more halo;

or R⁵ and R⁶, together with the atoms to which they are attached, form aring containing one or two heteroatoms selected from O, N, and S,wherein the ring is optionally substituted with one or more R⁵⁰; and

R⁵⁰ is C₁₋₆alkyl.

The present invention also provides a pharmaceutical compositioncomprising at least one compound described herein, or a pharmaceuticallyacceptable salt thereof, and at least one pharmaceutically acceptableexcipient.

In one embodiment, the invention is a method of treating a disorderresponsive to inhibition of Btk in a subject comprising administering tosaid subject an effective amount of at least one compound describedherein, or a pharmaceutically acceptable salt thereof.

The present invention also includes the use of at least one compounddescribed herein, or a pharmaceutically acceptable salt thereof, for themanufacture of a medicament for the treatment of a disorder responsiveto inhibition of Btk. Also provided is a compound described herein, or apharmaceutically acceptable salt thereof for use in treating a disorderresponsive to inhibition of Btk.

Other features or advantages will be apparent from the followingdetailed description of several embodiments, and also from the appendedclaims.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 depicts an powder X-ray diffraction (PXRD) pattern of crystallineForm A of(R)-1-(tert-butyl)-N-(8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(oxetan-3-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1H-1,2,3-triazole-4-carboxamide.

FIG. 2 depicts differential scanning calorimetry (DSC) and thermalgravimetric analysis (TGA) profiles of crystalline Form A of(R)-1-(tert-butyl)-N-(8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(oxetan-3-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1H-1,2,3-triazole-4-carboxamide.

FIG. 3A shows solution ¹³C NMR spectrum of crystalline Form A of(R)-1-(tert-butyl)-N-(8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(oxetan-3-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1H-1,2,3-triazole-4-carboxamide.FIG. 3B shows solid state ¹³NMR spectrum of crystalline Form A.

FIG. 4 depicts an powder X-ray diffraction (PXRD) pattern of crystallineForm G of(R)-1-(tert-butyl)-N-(8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(oxetan-3-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1H-1,2,3-triazole-4-carboxamide.

FIG. 5 depicts differential scanning calorimetry (DSC) and thermalgravimetric analysis (TGA) profiles of crystalline Form G of(R)-1-(tert-butyl)-N-(8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(oxetan-3-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1H-1,2,3-triazole-4-carboxamide.

FIG. 6A shows solution ¹³C NMR spectrum of crystalline Form G of(R)-1-(tert-butyl)-N-(8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(oxetan-3-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1H-1,2,3-triazole-4-carboxamide.FIG. 6B shows solid state ¹³NMR spectrum of crystalline Form G.

DETAILED DESCRIPTION

The compounds or pharmaceutically acceptable salts thereof as describedherein, can have activity as Btk modulators. In particular, compounds orpharmaceutically acceptable salts thereof as described herein, can beBtk inhibitors.

In a second embodiment of the present invention, the compound isrepresented by formula (I), or a pharmaceutically acceptable saltthereof, wherein Q¹, Q² and Q³ are each independently CH—R³ and thedefinitions for the other variables are as defined in the firstembodiment.

In a third embodiment of the present invention, the compound isrepresented by formula (I), or a pharmaceutically acceptable saltthereof, wherein Q² is N(R²), Q¹ and Q³ are each independently CH—R³,and the definitions for the other variables are as defined in the firstembodiment.

In a fourth embodiment of the present invention, the compound isrepresented by formula (I), or a pharmaceutically acceptable saltthereof, wherein Q³ is N(R²), Q¹ and Q² are each independently CH—R³,and the definitions for the other variables are as defined in the firstembodiment.

In a fifth embodiment of the present invention, the compound isrepresented by formula (I), or a pharmaceutically acceptable saltthereof, wherein Q¹ is O, Q² and Q³ are each independently CH—R³; andthe definitions for the other variables are as defined in the firstembodiment.

In a sixth embodiment of the present invention, the compound isrepresented by formula (I), or a pharmaceutically acceptable saltthereof, W is CH; and the definitions for the other variables are asdefined in the first, second, third, fourth or fifth embodiment.

In a seventh embodiment of the present invention, the compound isrepresented by formula (I), or a pharmaceutically acceptable saltthereof, wherein Y is N; and the definitions for the other variables areas defined in the first, second, third, fourth, fifth or sixthembodiment.

In an eighth embodiment of the present invention, the compound of thepresent invention is represented by any one of the following formulas:

or a pharmaceutically acceptable salt thereof; and the definitions forthe variables are as defined in the first embodiment.

In a ninth embodiment of the present invention, the compound isrepresented by formula (I), (II), (III), (IV), (V), (II′), (III′), (IV′)or (V′), or a pharmaceutically acceptable salt thereof, wherein ring Ais selected from 1,2,3-oxadiazole, 1,3,4-oxadiazole, 1,2,4-oxadizole,1,2,3-thiadiazole, 1,3,4-thiadiazole, 1,2,4-thiadiazole, 1,2,3-triazole,and 1,2,4-triazole, each of which is optionally substituted with one ortwo R¹; and the definitions for the other variables are as defined inthe first, second, third, fourth, fifth, sixth, seventh or eighthembodiment.

In a tenth embodiment of the present invention, the compounds isrepresented by formula (I), (II), (III), (IV), (V), (II′), (III′), (IV′)or (V′), or a pharmaceutically acceptable salt thereof, wherein ring Ais represented by one of the following formula:

and the definitions for the other variables are as defined in the first,second, third, fourth, fifth, sixth, seventh or eighth embodiment.

In a eleventh embodiment of the present invention, the compound isrepresented by formula (I), (II), (III), (IV), (V), (II′), (III′), (IV′)or (V′), or a pharmaceutically acceptable salt thereof, wherein:

R¹ in each occurrence is independently C₁₋₆alkyl or C₃₋₅cycloalkyl;wherein said C₁₋₆alkyl and C₃₋₅cycloalkyl are optionally substitutedwith one to three R¹⁰;

R¹⁰ in each occurrence is independently selected from halo, —CN andC₁₋₆alkyl;

and the definitions for the other variables are as defined in the first,second, third, fourth, fifth, sixth, seventh, eighth, ninth or tenthembodiment.

In a twelfth embodiment of the present invention, the compound isrepresented by formula (I), (II), (III), (IV), (V), (II′), (III′), (IV′)or (V′), or a pharmaceutically acceptable salt thereof, wherein:

R¹ in each occurrence is independently C₁₋₄alkyl, cyclopropyl, orcyclobutyl; wherein said C₁₋₄alkyl, cyclopropyl and cyclobutyl areoptionally substituted with one to three R¹⁰;

R¹⁰ in each occurrence is independently selected from halo, —CN andC₁₋₃alkyl;

and the definitions for the other variables are as defined in the first,second, third, fourth, fifth, sixth, seventh, eighth, ninth or tenthembodiment.

In a thirteenth embodiment of the present invention, the compound isrepresented by formula (I), (II), (III), (IV), (V), (II′), (III′), (IV′)or (V′), or a pharmaceutically acceptable salt thereof, wherein:

R¹ in each occurrence is independently selected from —C(CH₃)₃,—CH(CH₃)₂, —C(CH₃)₂CHF₂, —C(CH₃)₂CF₃, —C(CH₃)₂CH₂F, —C(CH₃)₂CN,1-methylcyclopropyl, cyclobutyl, and 3,3-difluorocyclobutyl; and thedefinitions for the other variables are as defined in the first, second,third, fourth, fifth, sixth, seventh, eighth, ninth or tenth embodiment.

In a fourteenth embodiment of the present invention, the compound isrepresented by formula (I), (II), (III), (IV), (V), (II′), (III′), (IV′)or (V′), or a pharmaceutically acceptable salt thereof, wherein R¹ is—C(CH₃)₃; and the definitions for the other variables are as defined inthe first, second, third, fourth, fifth, sixth, seventh, eighth, ninthor tenth embodiment.

In a fifteenth embodiment of the present invention, the compound isrepresented by formula (I), (II), (III), (IV), (V), (II′), (III′), (IV′)or (V′), or a pharmaceutically acceptable salt thereof, wherein:

R² is selected from H, C₁₋₆alkyl, C₄₋₆cycloalkyl, saturated 4- to6-membered monocyclic heterocyclyl, —C(O)R^(2a), —C(O)₂R^(2a), and—S(O)₂R^(2a), wherein said C₁₋₆alkyl, C₄₋₆cycloalkyl, and saturated 4-to 6-membered monocyclic heterocyclyl are optionally substituted withone to three R²⁰;

R^(2a) in each occurrence is independently selected from H, C₁₋₆alkyl,C₄₋₆alkyl, and saturated 4- to 6-membered monocyclic heterocyclyl,wherein said C₁₋₆alkyl, 4- to 6-membered monocyclic carbocyclyl, andsaturated 4- to 6-membered monocyclic heterocyclyl in each occurrenceare optionally and independently substituted with one or more R²⁰;

R²⁰ in each occurrence is independently selected from C₁₋₆alkyl,C₄₋₆cycloalkyl, saturated 4- to 6-membered monocyclic heterocyclyl,halo, —CN, —N(R^(20a))₂, and —OR^(20a);

R^(20a) in each occurrence is independently H or C₁₋₆alkyl;

and the definitions for the other variables are as defined in the first,second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth,eleventh, twelfth, thirteenth or fourteen embodiment.

In a sixteenth embodiment, the compound is represented by formula (I),(II), (III), (IV), (V), (II′), (III′), (IV′) or (V′), or apharmaceutically acceptable salt thereof, wherein:

R² is selected from H, C₁₋₆alkyl, C₄₋₆cycloalkyl selected fromcyclobutyl, cyclopentyl and cyclohexyl, saturated 4- to 6-memberedmonocyclic heterocyclyl selected from azetidinyl, oxetanyl,pyrrolidinyl, tetrahydrofuranyl, thiolanyl, imidazolidinyl,pyrazolidinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl,isothiazolidinyl, dioxolanyl, dithiolanyl, oxathiolanyl, piperidinyl,tetrahydropyranyl, thianyl, piperazinyl, morpholinyl, thiomorpholinyl,and dioxanyl, —C(O)R^(2a), C(O)₂R^(2a), and —S(O)₂R^(2a), wherein saidC₁₋₆alkyl, C₄₋₆cycloalkyl and saturated 4- to 6-membered monocyclicheterocyclyl are optionally substituted with one to three R²⁰;

R^(2a) is C₁₋₆alkyl optionally and independently substituted with one tothree R²⁰;

R²⁰ in each occurrence is independently selected from C₁₋₃alkyl,cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, halo, —N(R^(20a))₂,and —OR^(20a);

R^(20a) in each occurrence is independently H or C₁₋₃alkyl; and

the definitions for the other variables are as defined in the first,second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth,eleventh, twelfth, thirteenth, fourteen or fifteenth embodiment.

In a seventeenth embodiment of the present invention, the compound isrepresented by formula (I), (II), (III), (IV), (V), (II′), (III′), (IV′)or (V′), or a pharmaceutically acceptable salt thereof, wherein:

R² is selected from H, C₁₋₆alkyl, cyclobutyl, cyclopentyl andcyclohexyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, —C(O)R^(2a),—C(O)₂R^(2a), and —S(O)₂R^(2a), wherein said C₁₋₆alkyl, cyclobutyl,cyclopentyl and cyclohexyl, oxetanyl, tetrahydrofuranyl, andtetrahydropyranyl are optionally substituted with one to three R²⁰;

R^(2a) is C₁₋₆alkyl optionally substituted with one R²⁰;

R²⁰ in each occurrence is independently selected from C₁₋₃alkyl,cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, halo, —N(R^(20a))₂,and —OR^(20a);

R^(20a) in each occurrence is independently H or methyl;

the definitions for the other variables are as defined in the first,second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth,eleventh, twelfth, thirteenth, fourteen or fifteenth embodiment.

In a eighteenth embodiment of the present invention, the compound isrepresented by formula (I), (II), (III), (IV), (V), (II′), (III′), (IV′)or (V′), or a pharmaceutically acceptable salt thereof, wherein R² isselected from —H, —SO₂CH₃, —C(═O)OC(CH₃)₃, —C(═O)CH₂N(CH₃)₂, —CH₃,—CH₂CH₃, —CH₂CH₂OH, —CH₂CH₂OCH₃, —CH₂CH₂OCH₂CH₃, —CH₂CH(CH₃)OH,—CH₂C(CH₃)₂OH, —CH₂CH₂CH₂OH, —CH₂CHF₂, —CH₂CF₃,

and the definitions for the other variables are as defined in the first,second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth,eleventh, twelfth, thirteenth, fourteen or fifteenth embodiment.

In a nineteenth embodiment of the present invention, the compound isrepresented by formula (I), (II), (III), (IV), (V), (II′), (III′), (IV′)or (V′), or a pharmaceutically acceptable salt thereof, wherein R² isselected from —CH₂CHF₂, —CH₂CF₃, —CH₂CH₂OH, —CH₂CH(CH₃)OH, —CH₂CH₂OCH₃,

In a twentieth embodiment of the present invention, the compound isrepresented by formula (I), (II), (III), (IV), (V), (II′), (III′), (IV′)or (V′), or a pharmaceutically acceptable salt thereof, wherein:

R³ is selected from H, C₁₋₆alkyl, C₄₋₆cycloalkyl, saturated 4- to6-membered monocyclic heterocyclyl, halo, —OR^(3a), —OC(O)R^(3a),—OC(O)N(R^(3a))₂, and —SR^(3a), wherein said C₁₋₆alkyl, C₄₋₆cycloalkyl,and saturated 4- to 6-membered monocyclic heterocyclyl are optionallysubstituted with one to three R³⁰;

R^(3a) in each occurrence is independently H or C₁₋₆alkyl, wherein saidC₁₋₆alkyl in each occurrence is optionally and independently substitutedwith one R³⁰;

R³⁰ in each occurrence is independently selected from C₁₋₆alkyl;

and the definitions for the other variables are as defined in the first,second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth,eleventh, twelfth, thirteenth, fourteen, fifteenth, seventeenth,eighteenth, or nineteenth embodiment.

In a twenty-first embodiment of the present invention, the compound isrepresented by formula (I), (II), (III), (IV), (V), (II′), (III′), (IV′)or (V′), or a pharmaceutically acceptable salt thereof, wherein R³ isselected from H, halo, and —OR^(3a); R^(3a) is independently H orC₁₋₃alkyl; and the definitions for the other variables are as defined inthe first, second, third, fourth, fifth, sixth, seventh, eighth, ninth,tenth, eleventh, twelfth, thirteenth, fourteen, fifteenth, seventeenth,eighteenth, or nineteenth embodiment.

In a twenty-second embodiment of the present invention, the compound isrepresented by formula (I), (II), (III), (IV), (V), (II′), (III′), (IV′)or (V′), or a pharmaceutically acceptable salt thereof, wherein R³ isselected from H, —F and —OH; and the definitions for the other variablesare as defined in the first, second, third, fourth, fifth, sixth,seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, fourteen,fifteenth, seventeenth, eighteenth, or nineteenth embodiment.

In a twenty-third embodiment of the present invention, the compound isrepresented by formula (I), (II), (III), (IV), (V), (II′), (III′), (IV′)or (V′), or a pharmaceutically acceptable salt thereof, wherein R⁴ is Hor C₁₋₃alkyl optionally substituted with one to three fluoro; and thedefinitions for the other variables are as defined in the first, second,third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh,twelfth, thirteenth, fourteen, fifteenth, seventeenth, eighteenth,nineteenth, twentieth, twenty-first or twenty-second embodiment.

In a twenty-fourth embodiment of the present invention, the compound isrepresented by formula (I), (II), (III), (IV), (V), (II′), (III′), (IV′)or (V′), or a pharmaceutically acceptable salt thereof, wherein R⁴ is Hor methyl; and the definitions for the other variables are as defined inthe first, second, third, fourth, fifth, sixth, seventh, eighth, ninth,tenth, eleventh, twelfth, thirteenth, fourteen, fifteenth, seventeenth,eighteenth, nineteenth, twentieth, twenty-first or twenty-secondembodiment.

In a twenty-fifth embodiment of the present invention, the compound isrepresented by formula (I), (II), (III), (IV), (V), (II′), (III′), (IV′)or (V′), or a pharmaceutically acceptable salt thereof, wherein R⁵ is Hor C₁₋₃alkyl optionally substituted with one to three fluoro; and thedefinitions for the other variables are as defined in the first, second,third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh,twelfth, thirteenth, fourteen, fifteenth, seventeenth, eighteenth,nineteenth, twentieth, twenty-first, twenty-second, twenty-third ortwenty-fourth embodiment.

In a twenty-sixth embodiment of the present invention, the compound isrepresented by formula (I), (II), (III), (IV), (V), (II′), (III′), (IV′)or (V′), or a pharmaceutically acceptable salt thereof, wherein R⁵ is H,methyl, ethyl or isopropyl; and the definitions for the other variablesare as defined in the first, second, third, fourth, fifth, sixth,seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, fourteen,fifteenth, seventeenth, eighteenth, nineteenth, twentieth, twenty-first,twenty-second, twenty-third or twenty-fourth embodiment.

In a twenty-seventh embodiment of the present invention, the compound isrepresented by formula (I), (II), (III), (IV), (V), (II′), (III′), (IV′)or (V′), or a pharmaceutically acceptable salt thereof, wherein R⁶ is Hor C₁₋₃alkyl optionally substituted with one to three fluoro; and thedefinitions for the other variables are as defined in the first, second,third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh,twelfth, thirteenth, fourteen, fifteenth, seventeenth, eighteenth,nineteenth, twentieth, twenty-first, twenty-second, twenty-third,twenty-fourth, twenty-fifth or twenty-sixth embodiment.

In a twenty-eighth embodiment of the present invention, the compound isrepresented by formula (I), (II), (III), (IV), (V), (II′), (III′), (IV′)or (V′), or a pharmaceutically acceptable salt thereof, wherein R⁶ is H,methyl or triflouromethyl; and the definitions for the other variablesare as defined in the first, second, third, fourth, fifth, sixth,seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, fourteen,fifteenth, seventeenth, eighteenth, nineteenth, twentieth, twenty-first,twenty-second, twenty-third, twenty-fourth, twenty-fifth or twenty-sixthembodiment.

In a twenty-ninth embodiment of the present invention, the compound isrepresented by formula (I), (II), (III), (IV), (V), (II′), (III′), (IV′)or (V′), or a pharmaceutically acceptable salt thereof, wherein R⁵ andR⁶ together with the atoms to which they are attached, form a 5- to6-membered saturated heterocyclic ring containing one or two heteroatomsselected from O, N, and S, wherein the ring is optionally substitutedwith one R⁵⁰; R⁵⁰ is a C₁₋₃alkyl; and the definitions for the othervariables are as defined in the first, second, third, fourth, fifth,sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth,fourteen, fifteenth, seventeenth, eighteenth, nineteenth, twentieth,twenty-first, twenty-second, twenty-third, or twenty-fourth embodiment.In a more specific embodiment, the 5- to 6-membered saturatedheterocyclic ring heterocyclic ring is pyrrolindine, piperazine orN-methylpiperazine.

In a thirtieth embodiment of the present invention, the compound isrepresented by the following formula:

or a pharmaceutically acceptable salt thereof, wherein:

ring A is represented by one of the following formula:

R¹ is C₁₋₆alkyl;

R² is C₁₋₆alkyl, oxetanyl, tetrahydrofuranyl, or tetrahydropyranyl,wherein said C₁₋₆alkyl is optionally substituted with one to three R²⁰;

R²⁰ for each occurrence is independently halo or —OR^(20a);

R^(20a) H or C₁₋₃alkyl;

R³ is H; and

R⁵ is H or C₁₋₃alkyl.

In a thirty-first embodiment of the present invention, the compound isrepresented by formula (IIA), (IVA), (VA), (IIA′), (IVA′), or (VA′), ora pharmaceutically acceptable salt thereof, wherein R¹ is tert-butyl;and the definitions for the other variables are as defined in thethirtieth embodiment.

In a thirty-second embodiment of the present invention, the compound isrepresented by formula (IIA) or (IIA′), or a pharmaceutically acceptablesalt thereof, wherein R² is

—CH₂CHF₂, —CH₂CF₃, —CH₂CH₂OH, —CH₂CH₂OCH₃, or —CH₂C(CH₃)OH; and thedefinitions for the other variables are as defined in the thirtieth orthirty-first embodiment.

In a thirty-third embodiment of the present invention, the compound isrepresented by formula (IVA) to (IVA′), or a pharmaceutically acceptablesalt thereof, wherein R³ is H; and the definitions for the othervariables are as defined in the thirtieth, or thirty-first embodiment.

In a thirty-fourth embodiment of the present invention, the compound isrepresented by formula (IIA), (IVA), (VA), (IIA′), (IVA′), or (VA′), ora pharmaceutically acceptable salt thereof, wherein R⁵ is methyl orisopropyl; and the definitions for the other variables are as defined inthe thirtieth, thirty-first, thirty-second or thirty-third embodiment.

In a thirty-fifth embodiment of the present invention, the compound ofthe present invention is selected from:

-   5-(tert-butyl)-N-(7-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-1-yl)-1,2,4-oxadiazole-3-carboxamide,-   (S)-5-(tert-butyl)-N-(7-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-1-yl)-1,2,4-oxadiazole-3-carboxamide,-   (R)-5-(tert-butyl)-N-(7-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-1-yl)-1,2,4-oxadiazole-3-carboxamide,-   5-(tert-butyl)-N-(8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(oxetan-3-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1,2,4-oxadiazole-3-carboxamide,-   (R)-5-(tert-butyl)-N-(8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(oxetan-3-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1,2,4-oxadiazole-3-carboxamide,-   (S)-5-(tert-butyl)-N-(8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(oxetan-3-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1,2,4-oxadiazole-3-carboxamide,-   5-(tert-butyl)-N-(2-(2-hydroxyethyl)-8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1,2,4-oxadiazole-3-carboxamide,-   (R)-5-(tert-butyl)-N-(2-(2-hydroxyethyl)-8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1,2,4-oxadiazole-3-carboxamide,-   (S)-5-(tert-butyl)-N-(2-(2-hydroxyethyl)-8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1,2,4-oxadiazole-3-carboxamide,-   5-(tert-butyl)-N-(8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(methylsulfonyl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1,2,4-oxadiazole-3-carboxamide,-   (R)-5-(tert-butyl)-N-(8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(methylsulfonyl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1,2,4-oxadiazole-3-carboxamide,-   (S)-5-(tert-butyl)-N-(8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(methylsulfonyl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1,2,4-oxadiazole-3-carboxamide,    5-(tert-butyl)-N-(2-(3-hydroxycyclobutyl)-8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1,2,4-oxadiazole-3-carboxamide,-   (R)-5-(tert-butyl)-N-(2-(3-hydroxycyclobutyl)-8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1,2,4-oxadiazole-3-carboxamide,-   (S)-5-(tert-butyl)-N-(2-(3-hydroxycyclobutyl)-8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1,2,4-oxadiazole-3-carboxamide,-   5-(tert-butyl)-N-(8-(2-((1-ethyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(oxetan-3-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1,2,4-oxadiazole-3-carboxamide,-   (R)-5-(tert-butyl)-N-(8-(2-((1-ethyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(oxetan-3-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1,2,4-oxadiazole-3-carboxamide,-   (S)-5-(tert-butyl)-N-(8-(2-((1-ethyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(oxetan-3-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1,2,4-oxadiazole-3-carboxamide,-   5-(tert-butyl)-N-(8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(tetrahydro-2H-pyran-4-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1,2,4-oxadiazole-3-carboxamide,-   (R)-5-(tert-butyl)-N-(8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(tetrahydro-2H-pyran-4-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1,2,4-oxadiazole-3-carboxamide,-   (S)-5-(tert-butyl)-N-(8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(tetrahydro-2H-pyran-4-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1,2,4-oxadiazole-3-carboxamide,-   5-(tert-butyl)-N-(8-(2-((1,5-dimethyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(2-hydroxyethyl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1,2,4-oxadiazole-3-carboxamide,-   (R)-5-(tert-butyl)-N-(8-(2-((1,5-dimethyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(2-hydroxyethyl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1,2,4-oxadiazole-3-carboxamide,-   (S)-5-(tert-butyl)-N-(8-(2-((1,5-dimethyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(2-hydroxyethyl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1,2,4-oxadiazole-3-carboxamide,-   5-(tert-butyl)-N-(8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(tetrahydrofuran-3-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1,2,4-oxadiazole-3-carboxamide,-   5-(tert-butyl)-N—((R)-8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-((R)-tetrahydrofuran-3-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1,2,4-oxadiazole-3-carboxamide,-   5-(tert-butyl)-N—((R)-8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-((S)-tetrahydrofuran-3-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1,2,4-oxadiazole-3-carboxamide,-   5-(tert-butyl)-N—((S)-8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-((R)-tetrahydrofuran-3-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1,2,4-oxadiazole-3-carboxamide,-   5-(tert-butyl)-N—((S)-8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-((S)-tetrahydrofuran-3-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1,2,4-oxadiazole-3-carboxamide,-   5-(tert-butyl)-N-(8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(2,2,2-trifluoroethyl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1,2,4-oxadiazole-3-carboxamide-   (R)-5-(tert-butyl)-N-(8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(2,2,2-trifluoroethyl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1,2,4-oxadiazole-3-carboxamide,-   (S)-5-(tert-butyl)-N-(8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(2,2,2-trifluoroethyl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1,2,4-oxadiazole-3-carboxamide,    5-(tert-butyl)-N-(8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(tetrahydro-2H-pyran-4-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1,3,4-oxadiazole-2-carboxamide,-   (R)-5-(tert-butyl)-N-(8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(tetrahydro-2H-pyran-4-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1,3,4-oxadiazole-2-carboxamide,-   (S)-5-(tert-butyl)-N-(8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(tetrahydro-2H-pyran-4-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1,3,4-oxadiazole-2-carboxamide,-   5-(tert-butyl)-N-(8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(oxetan-3-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1,3,4-oxadiazole-2-carboxamide,-   (R)-5-(tert-butyl)-N-(8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(oxetan-3-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1,3,4-oxadiazole-2-carboxamide,-   (S)-5-(tert-butyl)-N-(8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(oxetan-3-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1,3,4-oxadiazole-2-carboxamide,-   5-(tert-butyl)-N-(8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(methylsulfonyl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1,3,4-oxadiazole-2-carboxamide-   (R)-5-(tert-butyl)-N-(8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(methylsulfonyl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1,3,4-oxadiazole-2-carboxamide,-   (S)-5-(tert-butyl)-N-(8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(methylsulfonyl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1,3,4-oxadiazole-2-carboxamide,-   5-(tert-butyl)-N-(2-(2-hydroxyethyl)-8-(2-((1-isopropyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1,3,4-oxadiazole-2-carboxamide-   (R)-5-(tert-butyl)-N-(2-(2-hydroxyethyl)-8-(2-((1-isopropyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1,3,4-oxadiazole-2-carboxamide,-   (S)-5-(tert-butyl)-N-(2-(2-hydroxyethyl)-8-(2-((1-isopropyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1,3,4-oxadiazole-2-carboxamide,-   5-(tert-butyl)-N-(8-(2-((1-isopropyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(oxetan-3-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1,3,4-oxadiazole-2-carboxamide-   (R)-5-(tert-butyl)-N-(8-(2-((1-isopropyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(oxetan-3-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1,3,4-oxadiazole-2-carboxamide,-   (S)-5-(tert-butyl)-N-(8-(2-((1-isopropyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(oxetan-3-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1,3,4-oxadiazole-2-carboxamide,-   5-(tert-butyl)-N-(8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(2,2,2-trifluoroethyl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1,3,4-oxadiazole-2-carboxamide-   (R)-5-(tert-butyl)-N-(8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(2,2,2-trifluoroethyl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1,3,4-oxadiazole-2-carboxamide,-   (S)-5-(tert-butyl)-N-(8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(2,2,2-trifluoroethyl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1,3,4-oxadiazole-2-carboxamide-   5-(tert-butyl)-N-(2-(2-hydroxyethyl)-8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1,3,4-oxadiazole-2-carboxamide,-   (R)-5-(tert-butyl)-N-(2-(2-hydroxyethyl)-8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1,3,4-oxadiazole-2-carboxamide,-   (S)-5-(tert-butyl)-N-(2-(2-hydroxyethyl)-8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1,3,4-oxadiazole-2-carboxamide,-   5-(tert-butyl)-N-(8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(tetrahydrofuran-3-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1,3,4-oxadiazole-2-carboxamide,-   5-(tert-butyl)-N—((R)-8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-((R)-tetrahydrofuran-3-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1,3,4-oxadiazole-2-carboxamide,-   5-(tert-butyl)-N—((R)-8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-((S)-tetrahydrofuran-3-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1,3,4-oxadiazole-2-carboxamide,-   5-(tert-butyl)-N—((S)-8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-((R)-tetrahydrofuran-3-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1,3,4-oxadiazole-2-carboxamide,-   5-(tert-butyl)-N—((S)-8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-((S)-tetrahydrofuran-3-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1,3,4-oxadiazole-2-carboxamide,-   5-(tert-butyl)-N-(2-(2-hydroxypropyl)-8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1,3,4-oxadiazole-2-carboxamide,-   5-(tert-butyl)-N—((R)-2-((S)-2-hydroxypropyl)-8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1,3,4-oxadiazole-2-carboxamide,-   5-(tert-butyl)-N—((R)-2-((R)-2-hydroxypropyl)-8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1,3,4-oxadiazole-2-carboxamide-   5-(tert-butyl)-N—((S)-2-((R)-2-hydroxypropyl)-8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1,3,4-oxadiazole-2-carboxamide,-   5-(tert-butyl)-N—((S)-2-((S)-2-hydroxypropyl)-8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1,3,4-oxadiazole-2-carboxamide,-   5-(tert-butyl)-N-(2-((S)-2-hydroxypropyl)-8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1,3,4-oxadiazole-2-carboxamide,-   5-(tert-butyl)-N-(2-((R)-2-hydroxypropyl)-8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1,3,4-oxadiazole-2-carboxamide,-   5-(tert-butyl)-N—((R)-2-((R)-2-hydroxypropyl)-8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1,3,4-oxadiazole-2-carboxamide,-   5-(tert-butyl)-N—((S)-2-((S)-2-hydroxypropyl)-8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1,3,4-oxadiazole-2-carboxamide-   5-(tert-butyl)-N—((S)-2-((R)-2-hydroxypropyl)-8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1,3,4-oxadiazole-2-carboxamide,-   5-(tert-butyl)-N-(8-(2-((1-ethyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(oxetan-3-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1,2,4-oxadiazole-3-carboxamide,-   (R)-1-(tert-butyl)-N-(8-(2-((1-ethyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(oxetan-3-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1H-1,2,3-triazole-4-carboxamide-   (S)-1-(tert-butyl)-N-(8-(2-((1-ethyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(oxetan-3-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1H-1,2,3-triazole-4-carboxamide-   1-(tert-butyl)-N-(8-(2-((1-isopropyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(oxetan-3-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1H-1,2,3-triazole-4-carboxamide,-   (R)-1-(tert-butyl)-N-(8-(2-((1-isopropyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(oxetan-3-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1H-1,2,3-triazole-4-carboxamide,    (S)-1-(tert-butyl)-N-(8-(2-((1-isopropyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(oxetan-3-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1H-1,2,3-triazole-4-carboxamide,-   1-(tert-butyl)-N-(8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(tetrahydrofuran-3-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1H-1,2,3-triazole-4-carboxamide,-   1-(tert-butyl)-N-((5R)-8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(tetrahydrofuran-3-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1H-1,2,3-triazole-4-carboxamide,-   1-(tert-butyl)-N—((R)-8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-((R)-tetrahydrofuran-3-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1H-1,2,3-triazole-4-carboxamide,-   1-(tert-butyl)-N—((R)-8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-((S)-tetrahydrofuran-3-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1H-1,2,3-triazole-4-carboxamide,-   1-(tert-butyl)-N—((S)-8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-((S)-tetrahydrofuran-3-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1H-1,2,3-triazole-4-carboxamide,-   1-(tert-butyl)-N—((S)-8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-((R)-tetrahydrofuran-3-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1H-1,2,3-triazole-4-carboxamide,-   1-(tert-butyl)-N-(8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(oxetan-3-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1H-1,2,3-triazole-4-carboxamide,-   (R)-1-(tert-butyl)-N-(8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(oxetan-3-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1H-1,2,3-triazole-4-carboxamide,-   (S)-1-(tert-butyl)-N-(8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(oxetan-3-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1H-1,2,3-triazole-4-carboxamide,-   1-(tert-butyl)-N-(8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(2,2,2-trifluoroethyl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1H-1,2,3-triazole-4-carboxamide,-   (R)-1-(tert-butyl)-N-(8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(2,2,2-trifluoroethyl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1H-1,2,3-triazole-4-carboxamide,-   (S)-1-(tert-butyl)-N-(8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(2,2,2-trifluoroethyl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1H-1,2,3-triazole-4-carboxamide,-   1-(tert-butyl)-N-(2-(2-hydroxypropyl)-8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1H-1,2,3-triazole-4-carboxamide,-   1-(tert-butyl)-N—((R)-2-((R)-2-hydroxypropyl)-8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1H-1,2,3-triazole-4-carboxamide,-   1-(tert-butyl)-N—((R)-2-((S)-2-hydroxypropyl)-8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1H-1,2,3-triazole-4-carboxamide,-   1-(tert-butyl)-N—((S)-2-((R)-2-hydroxypropyl)-8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1H-1,2,3-triazole-4-carboxamide,-   1-(tert-butyl)-N—((S)-2-((S)-2-hydroxypropyl)-8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1H-1,2,3-triazole-4-carboxamide,-   1-(tert-butyl)-N-(2-(2-methoxyethyl)-8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1H-1,2,3-triazole-4-carboxamide,-   (R)-1-(tert-butyl)-N-(2-(2-methoxyethyl)-8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1H-1,2,3-triazole-4-carboxamide,-   (S)-1-(tert-butyl)-N-(2-(2-methoxyethyl)-8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1H-1,2,3-triazole-4-carboxamide,-   5-(tert-butyl)-N-(2-(2,2-difluoroethyl)-8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1,3,4-oxadiazole-2-carboxamide,-   (R)-5-(tert-butyl)-N-(2-(2,2-difluoroethyl)-8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1,3,4-oxadiazole-2-carboxamide,-   (S)-5-(tert-butyl)-N-(2-(2,2-difluoroethyl)-8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1,3,4-oxadiazole-2-carboxamide,-   5-(tert-butyl)-N-(2-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl)-1,2,4-oxadiazole-3-carboxamide,-   (R)-5-(tert-butyl)-N-(2-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl)-1,2,4-oxadiazole-3-carboxamide,-   (S)-5-(tert-butyl)-N-(2-(2-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl)-1,2,4-oxadiazole-3-carboxamide,-   N-(2-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl)-5-(1-methylcyclopropyl)-1,2,4-oxadiazole-3-carboxamide-   (R)—N-(2-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl)-5-(1-methylcyclopropyl)-1,2,4-oxadiazole-3-carboxamide,-   (S)—N-(2-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl)-5-(1-methylcyclopropyl)-1,2,4-oxadiazole-3-carboxamide,-   5-(tert-butyl)-N-(2-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyridin-4-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl)-1,2,4-oxadiazole-3-carboxamide,-   (R)-5-(tert-butyl)-N-(2-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyridin-4-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl)-1,2,4-oxadiazole-3-carboxamide,-   (S)-5-(tert-butyl)-N-(2-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyridin-4-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl)-1,2,4-oxadiazole-3-carboxamide,-   5-(tert-butyl)-N-(2-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl)-1,3,4-oxadiazole-2-carboxamide,-   (R)-5-(tert-butyl)-N-(2-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl)-1,3,4-oxadiazole-2-carboxamide,-   (S)-5-(tert-butyl)-N-(2-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl)-1,3,4-oxadiazole-2-carboxamide,-   3-(tert-butyl)-N-(2-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl)-1,2,4-oxadiazole-5-carboxamide,-   (R)-3-(tert-butyl)-N-(2-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl)-1,2,4-oxadiazole-5-carboxamide,-   (S)-3-(tert-butyl)-N-(2-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl)-1,2,4-oxadiazole-5-carboxamide,-   5-(tert-butyl)-N-(8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydrobenzo[b]oxepin-5-yl)-1,3,4-oxadiazole-2-carboxamide,-   (R)-5-(tert-butyl)-N-(8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydrobenzo[b]oxepin-5-yl)-1,3,4-oxadiazole-2-carboxamide,-   (S)-5-(tert-butyl)-N-(8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydrobenzo[b]oxepin-5-yl)-1,3,4-oxadiazole-2-carboxamide,-   5-(tert-butyl)-N-(8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydrobenzo[b]oxepin-5-yl)-1,2,4-oxadiazole-2-carboxamide,-   (R)-5-(tert-butyl)-N-(8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydrobenzo[b]oxepin-5-yl)-1,2,4-oxadiazole-2-carboxamide,-   (S)-5-(tert-butyl)-N-(8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydrobenzo[b]oxepin-5-yl)-1,2,4-oxadiazole-2-carboxamide,-   5-(tert-butyl)-N-(3-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-6,7,8,9-tetrahydro-5H-cyclohepta[c]pyridin-9-yl)-1,3,4-oxadiazole-2-carboxamide,-   (R)-5-(tert-butyl)-N-(3-(2-((i-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-6,7,8,9-tetrahydro-5H-cyclohepta[c]pyridin-9-yl)-1,3,4-oxadiazole-2-carboxamide,-   (S)-5-(tert-butyl)-N-(3-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-6,7,8,9-tetrahydro-5H-cyclohepta[c]pyridin-9-yl)-1,3,4-oxadiazole-2-carboxamide,-   5-(tert-butyl)-N-(3-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-6,7,8,9-tetrahydro-5H-cyclohepta[c]pyridin-9-yl)-1,2,4-oxadiazole-3-carboxamide,-   (R)-5-(tert-butyl)-N-(3-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-6,7,8,9-tetrahydro-5H-cyclohepta[c]pyridin-9-yl)-1,2,4-oxadiazole-3-carboxamide,-   (S)-5-(tert-butyl)-N-(3-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-6,7,8,9-tetrahydro-5H-cyclohepta[c]pyridin-9-yl)-1,2,4-oxadiazole-3-carboxamide,-   1-(tert-butyl)-N-(3-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyridin-4-yl)-6,7,8,9-tetrahydro-5H-cyclohepta[c]pyridin-9-yl)-1H-1,2,3-triazole-4-carboxamide,-   (R)-1-(tert-butyl)-N-(3-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyridin-4-yl)-6,7,8,9-tetrahydro-5H-cyclohepta[c]pyridin-9-yl)-1H-1,2,3-triazole-4-carboxamide,-   (S)-1-(tert-butyl)-N-(3-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyridin-4-yl)-6,7,8,9-tetrahydro-5H-cyclohepta[c]pyridin-9-yl)-1H-1,2,3-triazole-4-carboxamide,-   5-(tert-butyl)-N-(3-(2-hydroxyethyl)-7-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-1-yl)-1,3,4-oxadiazole-2-carboxamide,-   (R)-5-(tert-butyl)-N-(3-(2-hydroxyethyl)-7-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-1-yl)-1,3,4-oxadiazole-2-carboxamide,-   (S)-5-(tert-butyl)-N-(3-(2-hydroxyethyl)-7-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-1-yl)-1,3,4-oxadiazole-2-carboxamide,-   5-(tert-butyl)-N-(7-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-3-(methylsulfonyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-1-yl)-1,3,4-oxadiazole-2-carboxamide,-   (R)-5-(tert-butyl)-N-(7-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-3-(methylsulfonyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-1-yl)-1,3,4-oxadiazole-2-carboxamide,-   (S)-5-(tert-butyl)-N-(7-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-3-(methylsulfonyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-1-yl)-1,3,4-oxadiazole-2-carboxamide-   5-(tert-butyl)-N-(7-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-3-(oxetan-3-yl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-1-yl)-1,3,4-oxadiazole-2-carboxamide,-   (R)-5-(tert-butyl)-N-(7-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-3-(oxetan-3-yl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-1-yl)-1,3,4-oxadiazole-2-carboxamide,-   (S)-5-(tert-butyl)-N-(7-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-3-(oxetan-3-yl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-1-yl)-1,3,4-oxadiazole-2-carboxamide,-   5-(tert-butyl)-N-(7-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-3-(tetrahydrofuran-3-yl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-1-yl)-1,3,4-oxadiazole-2-carboxamide,-   5-(tert-butyl)-N—((R)-7-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-3-((S)-tetrahydrofuran-3-yl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-1-yl)-1,3,4-oxadiazole-2-carboxamide-   5-(tert-butyl)-N—((R)-7-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-3-((R)-tetrahydrofuran-3-yl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-1-yl)-1,3,4-oxadiazole-2-carboxamide-   5-(tert-butyl)-N—((S)-7-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-3-((S)-tetrahydrofuran-3-yl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-1-yl)-1,3,4-oxadiazole-2-carboxamide-   5-(tert-butyl)-N—((S)-7-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-3-((R)-tetrahydrofuran-3-yl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-1-yl)-1,3,4-oxadiazole-2-carboxamide-   5-(tert-butyl)-N-(3-(2-hydroxy-2-methylpropyl)-7-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-1-yl)-1,3,4-oxadiazole-2-carboxamide,-   (R)-5-(tert-butyl)-N-(3-(2-hydroxy-2-methylpropyl)-7-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-1-yl)-1,3,4-oxadiazole-2-carboxamide,-   (S)-5-(tert-butyl)-N-(3-(2-hydroxy-2-methylpropyl)-7-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-1-yl)-1,3,4-oxadiazole-2-carboxamide,-   1-(tert-butyl)-N-(7-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-1-yl)-1H-1,2,3-triazole-4-carboxamide,-   (R)-1-(tert-butyl)-N-(7-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-1-yl)-1H-1,2,3-triazole-4-carboxamide,-   (S)-1-(tert-butyl)-N-(7-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-1-yl)-1H-1,2,3-triazole-4-carboxamide,-   1-(tert-butyl)-N-(3-methyl-7-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-1-yl)-1H-1,2,3-triazole-4-carboxamide,-   (R)-1-(tert-butyl)-N-(3-methyl-7-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-1-yl)-1H-1,2,3-triazole-4-carboxamide,-   (S)-1-(tert-butyl)-N-(3-methyl-7-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-1-yl)-1H-1,2,3-triazole-4-carboxamide,-   1-(tert-butyl)-N-(3-(2-hydroxyethyl)-7-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-1-yl)-1H-1,2,3-triazole-4-carboxamide,-   (R)-1-(tert-butyl)-N-(3-(2-hydroxyethyl)-7-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-1-yl)-1H-1,2,3-triazole-4-carboxamide,-   (S)-1-(tert-butyl)-N-(3-(2-hydroxyethyl)-7-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-1-yl)-1H-1,2,3-triazole-4-carboxamide,-   5-(tert-butyl)-N-(8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(2,2,2-trifluoroethyl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1,2,4-oxadiazole-3-carboxamide,-   (R)-5-(tert-butyl)-N-(8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(2,2,2-trifluoroethyl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1,2,4-oxadiazole-3-carboxamide-   (S)-5-(tert-butyl)-N-(8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(2,2,2-trifluoroethyl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1,2,4-oxadiazole-3-carboxamide    5-(tert-butyl)-N-(2-(2-(dimethylamino)acetyl)-8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1,2,4-oxadiazole-3-carboxamide,-   (R)-5-(tert-butyl)-N-(2-(2-(dimethylamino)acetyl)-8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1,2,4-oxadiazole-3-carboxamide,-   (S)-5-(tert-butyl)-N-(2-(2-(dimethylamino)acetyl)-8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1,2,4-oxadiazole-3-carboxamide,-   N-(2-(2-hydroxyethyl)-8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-5-(1,1,1-trifluoro-2-methylpropan-2-yl)-1,3,4-oxadiazole-2-carboxamide,-   (R)—N-(2-(2-hydroxyethyl)-8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-5-(1,1,1-trifluoro-2-methylpropan-2-yl)-1,3,4-oxadiazole-2-carboxamide,-   (S)—N-(2-(2-hydroxyethyl)-8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-5-(1,1,1-trifluoro-2-methylpropan-2-yl)-1,3,4-oxadiazole-2-carboxamide,-   N-(2-methyl-8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-5-(1,1,1-trifluoro-2-methylpropan-2-yl)-1,3,4-oxadiazole-2-carboxamide,-   (R)—N-(2-methyl-8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-5-(1,1,1-trifluoro-2-methylpropan-2-yl)-1,3,4-oxadiazole-2-carboxamide,-   (S)—N-(2-methyl-8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-5-(1,1,1-trifluoro-2-methylpropan-2-yl)-1,3,4-oxadiazole-2-carboxamide,-   5-(1,1-difluoro-2-methylpropan-2-yl)-N-(8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(oxetan-3-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1,3,4-oxadiazole-2-carboxamide,-   (R)-5-(1,1-difluoro-2-methylpropan-2-yl)-N-(8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(oxetan-3-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1,3,4-oxadiazole-2-carboxamide,-   (S)-5-(1,1-difluoro-2-methylpropan-2-yl)-N-(8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(oxetan-3-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1,3,4-oxadiazole-2-carboxamide,-   5-(1,1-difluoro-2-methylpropan-2-yl)-N-(2-(2-hydroxypropyl)-8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1,3,4-oxadiazole-2-carboxamide,-   5-(1,1-difluoro-2-methylpropan-2-yl)-N-(2-((S)-2-hydroxypropyl)-8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1,3,4-oxadiazole-2-carboxamide,-   (R)-5-(1,1-difluoro-2-methylpropan-2-yl)-N-(2-((S)-2-hydroxypropyl)-8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1,3,4-oxadiazole-2-carboxamide,-   (R)-5-(1,1-difluoro-2-methylpropan-2-yl)-N-(2-((R)-2-hydroxypropyl)-8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1,3,4-oxadiazole-2-carboxamide,-   (S)-5-(1,1-difluoro-2-methylpropan-2-yl)-N-(2-((R)-2-hydroxypropyl)-8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1,3,4-oxadiazole-2-carboxamide,-   (S)-5-(1,1-difluoro-2-methylpropan-2-yl)-N-(2-((S)-2-hydroxypropyl)-8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1,3,4-oxadiazole-2-carboxamide,-   5-(1-fluoro-2-methylpropan-2-yl)-N-(8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(oxetan-3-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1,3,4-oxadiazole-2-carboxamide,-   (R)-5-(1-fluoro-2-methylpropan-2-yl)-N-(8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(oxetan-3-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1,3,4-oxadiazole-2-carboxamide-   (S)-5-(1-fluoro-2-methylpropan-2-yl)-N-(8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(oxetan-3-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1,3,4-oxadiazole-2-carboxamide,-   5-(1-fluoro-2-methylpropan-2-yl)-N-(2-(2-hydroxypropyl)-8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1,3,4-oxadiazole-2-carboxamide,-   5-(1-fluoro-2-methylpropan-2-yl)-N-(2-((S)-2-hydroxypropyl)-8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1,3,4-oxadiazole-2-carboxamide,-   (R)-5-(1-fluoro-2-methylpropan-2-yl)-N-(2-((S)-2-hydroxypropyl)-8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1,3,4-oxadiazole-2-carboxamide,-   (R)-5-(1-fluoro-2-methylpropan-2-yl)-N-(2-((R)-2-hydroxypropyl)-8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1,3,4-oxadiazole-2-carboxamide,-   (S)-5-(1-fluoro-2-methylpropan-2-yl)-N-(2-((R)-2-hydroxypropyl)-8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1,3,4-oxadiazole-2-carboxamide,-   (S)-5-(1-fluoro-2-methylpropan-2-yl)-N-(2-((S)-2-hydroxypropyl)-8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1,3,4-oxadiazole-2-carboxamide,-   5-cyclobutyl-N-(2-methyl-8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1,3,4-oxadiazole-2-carboxamide,-   (R)-5-cyclobutyl-N-(2-methyl-8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1,3,4-oxadiazole-2-carboxamide,-   (S)-5-cyclobutyl-N-(2-methyl-8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1,3,4-oxadiazole-2-carboxamide,-   5-(2-cyanopropan-2-yl)-N-(2-methyl-8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1,3,4-oxadiazole-2-carboxamide,-   (R)-5-(2-cyanopropan-2-yl)-N-(2-methyl-8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1,3,4-oxadiazole-2-carboxamide,-   (S)-5-(2-cyanopropan-2-yl)-N-(2-methyl-8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1,3,4-oxadiazole-2-carboxamide,-   5-(2-cyanopropan-2-yl)-N-(2-(2-hydroxyethyl)-8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1,3,4-oxadiazole-2-carboxamide,-   (R)-5-(2-cyanopropan-2-yl)-N-(2-(2-hydroxyethyl)-8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1,3,4-oxadiazole-2-carboxamide,-   (S)-5-(2-cyanopropan-2-yl)-N-(2-(2-hydroxyethyl)-8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1,3,4-oxadiazole-2-carboxamide,-   1-isopropyl-N-(8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(oxetan-3-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1H-1,2,3-triazole-4-carboxamide,-   (R)-1-isopropyl-N-(8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(oxetan-3-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1H-1,2,3-triazole-4-carboxamide,-   (S)-1-isopropyl-N-(8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(oxetan-3-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1H-1,2,3-triazole-4-carboxamide,-   1-cyclobutyl-N-(8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(oxetan-3-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1H-1,2,3-triazole-4-carboxamide,-   (R)-1-cyclobutyl-N-(8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(oxetan-3-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1H-1,2,3-triazole-4-carboxamide,-   (S)-1-cyclobutyl-N-(8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(oxetan-3-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1H-1,2,3-triazole-4-carboxamide,-   5-(tert-butyl)-N-(8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(oxetan-3-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1,3,4-thiadiazole-2-carboxamide-   (R)-5-(tert-butyl)-N-(8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(oxetan-3-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1,3,4-thiadiazole-2-carboxamide,-   (S)-5-(tert-butyl)-N-(8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(oxetan-3-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1,3,4-thiadiazole-2-carboxamide,-   3-(tert-butyl)-N-(2-(3-hydroxycyclobutyl)-8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1,2,4-oxadiazole-5-carboxamide,-   (R)-3-(tert-butyl)-N-(2-(3-hydroxycyclobutyl)-8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1,2,4-oxadiazole-5-carboxamide,-   (S)-3-(tert-butyl)-N-(2-(3-hydroxycyclobutyl)-8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1,2,4-oxadiazole-5-carboxamide,-   1-(tert-butyl)-N-(8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1H-1,2,3-triazole-4-carboxamide,-   (R)-1-(tert-butyl)-N-(8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1H-1,2,3-triazole-4-carboxamide,-   (S)-1-(tert-butyl)-N-(8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1H-1,2,3-triazole-4-carboxamide,-   1-(tert-butyl)-N-(2-ethyl-8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1H-1,2,3-triazole-4-carboxamide,-   (R)-1-(tert-butyl)-N-(2-ethyl-8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1H-1,2,3-triazole-4-carboxamide,-   (S)-1-(tert-butyl)-N-(2-ethyl-8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1H-1,2,3-triazole-4-carboxamide,-   1-(tert-butyl)-N-(2-(3-hydroxycyclobutyl)-8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1H-1,2,3-triazole-4-carboxamide,-   (R)-1-(tert-butyl)-N-(2-(3-hydroxycyclobutyl)-8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1H-1,2,3-triazole-4-carboxamide,-   (S)-1-(tert-butyl)-N-(2-(3-hydroxycyclobutyl)-8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1H-1,2,3-triazole-4-carboxamide,-   1-(tert-butyl)-N-(8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(tetrahydro-2H-pyran-4-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1H-1,2,3-triazole-4-carboxamide,-   (R)-1-(tert-butyl)-N-(8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(tetrahydro-2H-pyran-4-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1H-1,2,3-triazole-4-carboxamide,-   (S)-1-(tert-butyl)-N-(8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(tetrahydro-2H-pyran-4-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1H-1,2,3-triazole-4-carboxamide,-   1-(tert-butyl)-N-(2-(2-hydroxyethyl)-8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1H-1,2,3-triazole-4-carboxamide,-   (R)-1-(tert-butyl)-N-(2-(2-hydroxyethyl)-8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1H-1,2,3-triazole-4-carboxamide,-   (S)-1-(tert-butyl)-N-(2-(2-hydroxyethyl)-8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1H-1,2,3-triazole-4-carboxamide,-   1-(tert-butyl)-N-(2-((R)-2-hydroxypropyl)-8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1H-1,2,3-triazole-4-carboxamide-   (R)-1-(tert-butyl)-N-(2-((R)-2-hydroxypropyl)-8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1H-1,2,3-triazole-4-carboxamide,-   (R)-1-(tert-butyl)-N-(2-((S)-2-hydroxypropyl)-8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1H-1,2,3-triazole-4-carboxamide,-   (S)-1-(tert-butyl)-N-(2-((R)-2-hydroxypropyl)-8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1H-1,2,3-triazole-4-carboxamide,-   (S)-1-(tert-butyl)-N-(2-((S)-2-hydroxypropyl)-8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1H-1,2,3-triazole-4-carboxamide,-   5-(tert-butyl)-N-(2-(2-hydroxypropyl)-8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1,2,4-oxadiazole-3-carboxamide-   5-(tert-butyl)-N-(2-((R)-2-hydroxypropyl)-8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1,2,4-oxadiazole-3-carboxamide,-   (R)-5-(tert-butyl)-N-(2-((R)-2-hydroxypropyl)-8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1,2,4-oxadiazole-3-carboxamide,-   (R)-5-(tert-butyl)-N-(2-((S)-2-hydroxypropyl)-8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1,2,4-oxadiazole-3-carboxamide,-   (S)-5-(tert-butyl)-N-(2-((R)-2-hydroxypropyl)-8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1,2,4-oxadiazole-3-carboxamide,-   (S)-5-(tert-butyl)-N-(2-((S)-2-hydroxypropyl)-8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1,2,4-oxadiazole-3-carboxamide,-   5-(tert-butyl)-N-(2-(2-methoxyethyl)-8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1,2,4-oxadiazole-3-carboxamide,-   (R)-5-(tert-butyl)-N-(2-(2-methoxyethyl)-8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1,2,4-oxadiazole-3-carboxamide,-   (S)-5-(tert-butyl)-N-(2-(2-methoxyethyl)-8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1,2,4-oxadiazole-3-carboxamide,-   5-(tert-butyl)-N-(8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(tetrahydrofuran-3-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1,3,4-oxadiazole-2-carboxamide,-   5-(tert-butyl)-N—((R)-8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-((R)-tetrahydrofuran-3-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1,3,4-oxadiazole-2-carboxamide,-   5-(tert-butyl)-N—((R)-8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-((S)-tetrahydrofuran-3-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1,3,4-oxadiazole-2-carboxamide,-   5-(tert-butyl)-N—((S)-8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-((R)-tetrahydrofuran-3-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1,3,4-oxadiazole-2-carboxamide,-   5-(tert-butyl)-N—((S)-8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-((S)-tetrahydrofuran-3-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1,3,4-oxadiazole-2-carboxamide,-   5-(tert-butyl)-N-(2-(3-hydroxycyclobutyl)-8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1,3,4-oxadiazole-2-carboxamide,-   (R)-5-(tert-butyl)-N-(2-(3-hydroxycyclobutyl)-8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1,3,4-oxadiazole-2-carboxamide,-   (S)-5-(tert-butyl)-N-(2-(3-hydroxycyclobutyl)-8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1,3,4-oxadiazole-2-carboxamide,-   5-(tert-butyl)-N-(2-ethyl-8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1,3,4-oxadiazole-2-carboxamide,-   (R)-5-(tert-butyl)-N-(2-ethyl-8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1,3,4-oxadiazole-2-carboxamide,-   (S)-5-(tert-butyl)-N-(2-ethyl-8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1,3,4-oxadiazole-2-carboxamide,-   5-(tert-butyl)-N-(2-(2-hydroxy-2-methylpropyl)-8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1,3,4-oxadiazole-2-carboxamide,-   5-tert-butyl-1,3,4-oxadiazole-2-carboxylic acid    {(R)-2-(2-hydroxy-2-methyl-propyl)-8-[2-(1-methyl-1H-pyrazol-4-ylamino)-pyrimidin-4-yl]-2,3,4,5-tetrahydro-1H-2-benzazepin-5-yl}-amide,-   (S)-5-(tert-butyl)-N-(2-(2-hydroxy-2-methylpropyl)-8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1,3,4-oxadiazole-2-carboxamide,-   5-(tert-butyl)-N-(2-(3-hydroxypropyl)-8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1,3,4-oxadiazole-2-carboxamide,-   (R)-5-(tert-butyl)-N-(2-(3-hydroxypropyl)-8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1,3,4-oxadiazole-2-carboxamide,-   (S)-5-(tert-butyl)-N-(2-(3-hydroxypropyl)-8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1,3,4-oxadiazole-2-carboxamide-   N-(8-(2-((1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(oxetan-3-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-5-(tert-butyl)-1,3,4-oxadiazole-2-carboxamide,-   (R)—N-(8-(2-((1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(oxetan-3-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-5-(tert-butyl)-1,3,4-oxadiazole-2-carboxamide,-   (S)—N-(8-(2-((1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(oxetan-3-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-5-(tert-butyl)-1,3,4-oxadiazole-2-carboxamide,-   (R)-5-(tert-butyl)-N-(8-(2-((5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)amino)pyrimidin-4-yl)-2-(2-hydroxyethyl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1,3,4-oxadiazole-2-carboxamide,-   (S)-5-(tert-butyl)-N-(8-(2-((5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)amino)pyrimidin-4-yl)-2-(2-hydroxyethyl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1,3,4-oxadiazole-2-carboxamide,-   5-(tert-butyl)-N-(8-(2-((5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)amino)pyrimidin-4-yl)-2-(2-hydroxyethyl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1,3,4-oxadiazole-2-carboxamide,-   (R)-1-(tert-butyl)-N-(8-(2-((5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)amino)pyrimidin-4-yl)-2-(2-hydroxyethyl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1H-1,2,3-triazole-4-carboxamide,-   (S)-1-(tert-butyl)-N-(8-(2-((5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)amino)pyrimidin-4-yl)-2-(2-hydroxyethyl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1H-1,2,3-triazole-4-carboxamide,-   1-(tert-butyl)-N-(8-(2-((5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)amino)pyrimidin-4-yl)-2-(2-hydroxyethyl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1H-1,2,3-triazole-4-carboxamide,-   N-(2-methyl-8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-5-(1-methylcyclopropyl)-1,3,4-oxadiazole-2-carboxamide,-   (R)—N-(2-methyl-8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-5-(1-methylcyclopropyl)-1,3,4-oxadiazole-2-carboxamide,-   (S)—N-(2-methyl-8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-5-(1-methylcyclopropyl)-1,3,4-oxadiazole-2-carboxamide,-   5-(tert-butyl)-N-(8-(2-((1-ethyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(tetrahydrofuran-3-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1,3,4-oxadiazole-2-carboxamide,-   5-(tert-butyl)-N—((R)-8-(2-((1-ethyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-((R)-tetrahydrofuran-3-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1,3,4-oxadiazole-2-carboxamide,-   5-(tert-butyl)-N—((R)-8-(2-((1-ethyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-((S)-tetrahydrofuran-3-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1,3,4-oxadiazole-2-carboxamide,-   5-(tert-butyl)-N—((S)-8-(2-((1-ethyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-((R)-tetrahydrofuran-3-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1,3,4-oxadiazole-2-carboxamide,-   5-(tert-butyl)-N—((S)-8-(2-((1-ethyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-((S)-tetrahydrofuran-3-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1,3,4-oxadiazole-2-carboxamide,-   5-(tert-butyl)-N-(8-(2-((1-ethyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(2-hydroxyethyl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1,3,4-oxadiazole-2-carboxamide,    (R)-5-(tert-butyl)-N-(8-(2-((1-ethyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(2-hydroxyethyl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1,3,4-oxadiazole-2-carboxamide,-   (S)-5-(tert-butyl)-N-(8-(2-((1-ethyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(2-hydroxyethyl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1,3,4-oxadiazole-2-carboxamide,-   5-(tert-butyl)-N-(2-methyl-8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1,3,4-oxadiazole-2-carboxamide,-   (R)-5-(tert-butyl)-N-(2-methyl-8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1,3,4-oxadiazole-2-carboxamide,-   (S)-5-(tert-butyl)-N-(2-methyl-8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1,3,4-oxadiazole-2-carboxamide,-   5-(tert-butyl)-N-(8-(2-((1,5-dimethyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(2-hydroxyethyl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1,3,4-oxadiazole-2-carboxamide,-   (R)-5-(tert-butyl)-N-(8-(2-((1,5-dimethyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(2-hydroxyethyl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1,3,4-oxadiazole-2-carboxamide,-   (S)-5-(tert-butyl)-N-(8-(2-((1,5-dimethyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(2-hydroxyethyl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1,3,4-oxadiazole-2-carboxamide,-   1-(tert-butyl)-N-(8-(2-((1,5-dimethyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(2-hydroxyethyl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1H-1,2,3-triazole-4-carboxamide,-   (R)-1-(tert-butyl)-N-(8-(2-((1,5-dimethyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(2-hydroxyethyl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1H-1,2,3-triazole-4-carboxamide,-   (S)-1-(tert-butyl)-N-(8-(2-((1,5-dimethyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(2-hydroxyethyl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1H-1,2,3-triazole-4-carboxamide,-   5-(tert-butyl)-N-(8-(2-((1,3-dimethyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(oxetan-3-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1,2,4-oxadiazole-3-carboxamide,-   (R)-5-(tert-butyl)-N-(8-(2-((1,3-dimethyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(oxetan-3-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1,2,4-oxadiazole-3-carboxamide,    (S)-5-(tert-butyl)-N-(8-(2-((1,3-dimethyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(oxetan-3-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1,2,4-oxadiazole-3-carboxamide,-   1-(tert-butyl)-N-(8-(2-((1,3-dimethyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(oxetan-3-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1H-1,2,3-triazole-4-carboxamide,-   (R)-1-(tert-butyl)-N-(8-(2-((1,3-dimethyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(oxetan-3-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1H-1,2,3-triazole-4-carboxamide,    (S)-1-(tert-butyl)-N-(8-(2-((1,3-dimethyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(oxetan-3-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1H-1,2,3-triazole-4-carboxamide,-   5-(tert-butyl)-N-(8-(2-((1,3-dimethyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(2-hydroxyethyl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1,2,4-oxadiazole-3-carboxamide,-   (R)-5-(tert-butyl)-N-(8-(2-((1,3-dimethyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(2-hydroxyethyl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1,2,4-oxadiazole-3-carboxamide,-   (S)-5-(tert-butyl)-N-(8-(2-((1,3-dimethyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(2-hydroxyethyl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1,2,4-oxadiazole-3-carboxamide,-   1-(tert-butyl)-N-(2-(2-hydroxyethyl)-8-(2-((1-isopropyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1H-1,2,3-triazole-4-carboxamide,-   (R)-1-(tert-butyl)-N-(2-(2-hydroxyethyl)-8-(2-((1-isopropyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1H-1,2,3-triazole-4-carboxamide,-   (S)-1-(tert-butyl)-N-(2-(2-hydroxyethyl)-8-(2-((1-isopropyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1H-1,2,3-triazole-4-carboxamide,-   5-(tert-butyl)-N-(2-(cyclopropylmethyl)-8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1,3,4-oxadiazole-2-carboxamide,-   (R)-5-(tert-butyl)-N-(2-(cyclopropylmethyl)-8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1,3,4-oxadiazole-2-carboxamide,-   (S)-5-(tert-butyl)-N-(2-(cyclopropylmethyl)-8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1,3,4-oxadiazole-2-carboxamide,-   5-(tert-butyl)-N-(8-(2-((1,3-dimethyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(2,2,2-trifluoroethyl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1,3,4-oxadiazole-2-carboxamide,-   (R)-5-(tert-butyl)-N-(8-(2-((1,3-dimethyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(2,2,2-trifluoroethyl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1,3,4-oxadiazole-2-carboxamide,-   (S)-5-(tert-butyl)-N-(8-(2-((1,3-dimethyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(2,2,2-trifluoroethyl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1,3,4-oxadiazole-2-carboxamide,-   5-(tert-butyl)-N-(2-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl)-1,3,4-oxadiazole-2-carboxamide,-   (R)-5-(tert-butyl)-N-(2-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl)-1,3,4-oxadiazole-2-carboxamide,-   (S)-5-(tert-butyl)-N-(2-(2-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl)-1,3,4-oxadiazole-2-carboxamide,-   N-(2-(2-((1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl)-5-(tert-butyl)-1,2,4-oxadiazole-3-carboxamide,-   (R)—N-(2-(2-((1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl)-5-(tert-butyl)-1,2,4-oxadiazole-3-carboxamide,-   (S)—N-(2-(2-((1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl)-5-(tert-butyl)-1,2,4-oxadiazole-3-carboxamide,-   5-(tert-butyl)-N-(2-(2-((5-methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-3-yl)amino)pyrimidin-4-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl)-1,2,4-oxadiazole-3-carboxamide,-   (R)-5-(tert-butyl)-N-(2-(2-((5-methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-3-yl)amino)pyrimidin-4-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl)-1,2,4-oxadiazole-3-carboxamide,-   (S)-5-(tert-butyl)-N-(2-(2-((5-methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-3-yl)amino)pyrimidin-4-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl)-1,2,4-oxadiazole-3-carboxamide,-   N-(2-(2-((1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl)-5-(tert-butyl)-1,3,4-oxadiazole-2-carboxamide,-   (R)—N-(2-(2-((1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl)-5-(tert-butyl)-1,3,4-oxadiazole-2-carboxamide,-   (S)—N-(2-(2-((1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl)-5-(tert-butyl)-1,3,4-oxadiazole-2-carboxamide,-   1-(tert-butyl)-N-(2-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl)-1H-1,2,3-triazole-4-carboxamide,-   (R)-1-(tert-butyl)-N-(2-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl)-1H-1,2,3-triazole-4-carboxamide,-   (S)-1-(tert-butyl)-N-(2-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl)-1H-1,2,3-triazole-4-carboxamide,-   5-(tert-butyl)-4-methyl-N-(2-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl)-4H-1,2,4-triazole-3-carboxamide,-   (R)-5-(tert-butyl)-4-methyl-N-(2-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl)-4H-1,2,4-triazole-3-carboxamide,-   (S)-5-(tert-butyl)-4-methyl-N-(2-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl)-4H-1,2,4-triazole-3-carboxamide,-   2-isopropyl-N-(2-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl)-2H-1,2,3-triazole-4-carboxamide,-   (R)-2-isopropyl-N-(2-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl)-2H-1,2,3-triazole-4-carboxamide,-   (S)-2-isopropyl-N-(2-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl)-2H-1,2,3-triazole-4-carboxamide,-   5-(tert-butyl)-N-(8-fluoro-2-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl)-1,3,4-oxadiazole-2-carboxamide,-   5-(tert-butyl)-N-((8S)-8-fluoro-2-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl)-1,3,4-oxadiazole-2-carboxamide,-   5-(tert-butyl)-N-((8R)-8-fluoro-2-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl)-1,3,4-oxadiazole-2-carboxamide,-   5-(tert-butyl)-N-((5R,8S)-8-fluoro-2-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl)-1,3,4-oxadiazole-2-carboxamide,-   5-(tert-butyl)-N-((5S,8R)-8-fluoro-2-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl)-1,3,4-oxadiazole-2-carboxamide,-   5-(tert-butyl)-N-((5R,8R)-8-fluoro-2-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl)-1,3,4-oxadiazole-2-carboxamide,-   5-(tert-butyl)-N-((5S,8S)-8-fluoro-2-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl)-1,3,4-oxadiazole-2-carboxamide,-   N-(8-fluoro-2-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl)-5-(1-methylcyclopropyl)-1,2,4-oxadiazole-3-carboxamide,-   N-((8S)-8-fluoro-2-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl)-5-(1-methylcyclopropyl)-1,2,4-oxadiazole-3-carboxamide,-   N-((8R)-8-fluoro-2-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl)-5-(1-methylcyclopropyl)-1,2,4-oxadiazole-3-carboxamide-   N-((5R,8S)-8-fluoro-2-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl)-5-(1-methylcyclopropyl)-1,2,4-oxadiazole-3-carboxamide-   N-((5S,8R)-8-fluoro-2-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl)-5-(1-methylcyclopropyl)-1,2,4-oxadiazole-3-carboxamide-   N-((5S,8S)-8-fluoro-2-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl)-5-(1-methylcyclopropyl)-1,2,4-oxadiazole-3-carboxamide-   N-((5S,8R)-8-fluoro-2-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl)-5-(1-methylcyclopropyl)-1,2,4-oxadiazole-3-carboxamide-   N-(2-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl)-5-(1-methylcyclopropyl)-1,3,4-oxadiazole-2-carboxamide,-   (R)—N-(2-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl)-5-(1-methylcyclopropyl)-1,3,4-oxadiazole-2-carboxamide,-   (S)—N-(2-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl)-5-(1-methylcyclopropyl)-1,3,4-oxadiazole-2-carboxamide,-   5-(tert-butyl)-N-(8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1,3,4-oxadiazole-2-carboxamide,-   (R)-5-(tert-butyl)-N-(8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1,3,4-oxadiazole-2-carboxamide,-   (S)-5-(tert-butyl)-N-(8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1,3,4-oxadiazole-2-carboxamide,-   5-cyclobutyl-N-(2-(2-hydroxyethyl)-8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1,3,4-oxadiazole-2-carboxamide,-   (R)-5-cyclobutyl-N-(2-(2-hydroxyethyl)-8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1,3,4-oxadiazole-2-carboxamide,-   (S)-5-cyclobutyl-N-(2-(2-hydroxyethyl)-8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1,3,4-oxadiazole-2-carboxamide,-   5-(tert-butyl)-N-(2-(2-ethoxyethyl)-8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1,3,4-oxadiazole-2-carboxamide,-   (R)-5-(tert-butyl)-N-(2-(2-ethoxyethyl)-8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1,3,4-oxadiazole-2-carboxamide,-   (S)-5-(tert-butyl)-N-(2-(2-ethoxyethyl)-8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1,3,4-oxadiazole-2-carboxamide,-   5-(tert-butyl)-N-(7-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-1-yl)-1,3,4-oxadiazole-2-carboxamide,-   (R)-5-(tert-butyl)-N-(7-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-1-yl)-1,3,4-oxadiazole-2-carboxamide,-   (S)-5-(tert-butyl)-N-(7-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-1-yl)-1,3,4-oxadiazole-2-carboxamide,-   1-(tert-butyl)-N-(7-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-3-(oxetan-3-yl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-1-yl)-1H-1,2,3-triazole-4-carboxamide,-   (R)-1-(tert-butyl)-N-(7-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-3-(oxetan-3-yl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-1-yl)-1H-1,2,3-triazole-4-carboxamide,-   (S)-1-(tert-butyl)-N-(7-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-3-(oxetan-3-yl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-1-yl)-1H-1,2,3-triazole-4-carboxamide,-   5-(tert-butyl)-N-(8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(tetrahydrofuran-3-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1,3,4-thiadiazole-2-carboxamide,-   5-(tert-butyl)-N—((R)-8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-((R)-tetrahydrofuran-3-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1,3,4-thiadiazole-2-carboxamide,-   5-(tert-butyl)-N—((R)-8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-((S)-tetrahydrofuran-3-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1,3,4-thiadiazole-2-carboxamide,-   5-(tert-butyl)-N—((S)-8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-((R)-tetrahydrofuran-3-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1,3,4-thiadiazole-2-carboxamide,-   5-(tert-butyl)-N—((S)-8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-((S)-tetrahydrofuran-3-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1,3,4-thiadiazole-2-carboxamide,-   5-(tert-butyl)-N-(3-methyl-7-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-1-yl)-1,3,4-oxadiazole-2-carboxamide,-   (R)-5-(tert-butyl)-N-(3-methyl-7-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-1-yl)-1,3,4-oxadiazole-2-carboxamide,-   (S)-5-(tert-butyl)-N-(3-methyl-7-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-1-yl)-1,3,4-oxadiazole-2-carboxamide,-   5-(tert-butyl)-N-(2-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl)-1,3,4-thiadiazole-2-carboxamide,-   (R)-5-(tert-butyl)-N-(2-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl)-1,3,4-thiadiazole-2-carboxamide,-   (S)-5-(tert-butyl)-N-(2-(2-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl)-1,3,4-thiadiazole-2-carboxamide,-   5-(tert-butyl)-N-(8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(2,2,2-trifluoroethyl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1,2,4-oxadiazole-3-carboxamide,-   tert-butyl    1-(5-(tert-butyl)-1,3,4-oxadiazole-2-carboxamido)-7-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-1,2,4,5-tetrahydro-3H-benzo[d]azepine-3-carboxylate,-   (R)-tert-butyl    1-(5-(tert-butyl)-1,3,4-oxadiazole-2-carboxamido)-7-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-1,2,4,5-tetrahydro-3H-benzo[d]azepine-3-carboxylate,-   (S)-tert-butyl    1-(5-(tert-butyl)-1,3,4-oxadiazole-2-carboxamido)-7-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-1,2,4,5-tetrahydro-3H-benzo[d]azepine-3-carboxylate,-   5-(tert-butyl)-N-(7-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-3-(2,2,2-trifluoroethyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-1-yl)-1,3,4-oxadiazole-2-carboxamide,-   (R)-5-(tert-butyl)-N-(7-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-3-(2,2,2-trifluoroethyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-1-yl)-1,3,4-oxadiazole-2-carboxamide,-   (S)-5-(tert-butyl)-N-(7-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-3-(2,2,2-trifluoroethyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-1-yl)-1,3,4-oxadiazole-2-carboxamide,-   5-(tert-butyl)-N-(3-(2-hydroxypropyl)-7-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-1-yl)-1,3,4-oxadiazole-2-carboxamide,-   5-(tert-butyl)-N-(3-((S)-2-hydroxypropyl)-7-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-1-yl)-1,3,4-oxadiazole-2-carboxamide,-   (R)-5-(tert-butyl)-N-(3-((S)-2-hydroxypropyl)-7-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-1-yl)-1,3,4-oxadiazole-2-carboxamide,-   (S)-5-(tert-butyl)-N-(3-((S)-2-hydroxypropyl)-7-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-1-yl)-1,3,4-oxadiazole-2-carboxamide,-   5-(tert-butyl)-N-(3-((R)-2-hydroxypropyl)-7-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-1-yl)-1,3,4-oxadiazole-2-carboxamide,-   (R)-5-(tert-butyl)-N-(3-((R)-2-hydroxypropyl)-7-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-1-yl)-1,3,4-oxadiazole-2-carboxamide,-   (S)-5-(tert-butyl)-N-(3-((R)-2-hydroxypropyl)-7-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-1-yl)-1,3,4-oxadiazole-2-carboxamide,-   5-(tert-butyl)-N-(7-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-3-(tetrahydro-2H-pyran-4-yl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-1-yl)-1,3,4-oxadiazole-2-carboxamide,-   (R)-5-(tert-butyl)-N-(7-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-3-(tetrahydro-2H-pyran-4-yl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-1-yl)-1,3,4-oxadiazole-2-carboxamide,-   (S)-5-(tert-butyl)-N-(7-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-3-(tetrahydro-2H-pyran-4-yl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-1-yl)-1,3,4-oxadiazole-2-carboxamide,-   5-(tert-butyl)-N-(3-(3-hydroxypropyl)-7-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-1-yl)-1,3,4-oxadiazole-2-carboxamide,-   (S)-5-(tert-butyl)-N-(3-(3-hydroxypropyl)-7-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-1-yl)-1,3,4-oxadiazole-2-carboxamide,-   (R)-5-(tert-butyl)-N-(3-(3-hydroxypropyl)-7-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-1-yl)-1,3,4-oxadiazole-2-carboxamide,-   5-(3,3-difluorocyclobutyl)-N-(2-methyl-8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1,3,4-oxadiazole-2-carboxamide,-   (R)-5-(3,3-difluorocyclobutyl)-N-(2-methyl-8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1,3,4-oxadiazole-2-carboxamide,-   (S)-5-(3,3-difluorocyclobutyl)-N-(2-methyl-8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1,3,4-oxadiazole-2-carboxamide,-   5-(3,3-difluorocyclobutyl)-N-(2-(2-hydroxyethyl)-8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1,3,4-oxadiazole-2-carboxamide,-   (R)-5-(3,3-difluorocyclobutyl)-N-(2-(2-hydroxyethyl)-8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1,3,4-oxadiazole-2-carboxamide,-   (S)-5-(3,3-difluorocyclobutyl)-N-(2-(2-hydroxyethyl)-8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1,3,4-oxadiazole-2-carboxamide,-   5-(tert-butyl)-N-(8-(2-((5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)amino)pyrimidin-4-yl)-2-(2-hydroxyethyl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1,2,4-oxadiazole-3-carboxamide,-   (R)-5-(tert-butyl)-N-(8-(2-((5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)amino)pyrimidin-4-yl)-2-(2-hydroxyethyl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1,2,4-oxadiazole-3-carboxamide,-   (S)-5-(tert-butyl)-N-(8-(2-((5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)amino)pyrimidin-4-yl)-2-(2-hydroxyethyl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1,2,4-oxadiazole-3-carboxamide,-   5-(tert-butyl)-N-(8-hydroxy-2-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl)-1,3,4-oxadiazole-2-carboxamide,-   (R)-5-(tert-butyl)-N-(8-hydroxy-2-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl)-1,3,4-oxadiazole-2-carboxamide,-   (S)-5-(tert-butyl)-N-(8-hydroxy-2-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl)-1,3,4-oxadiazole-2-carboxamide,-   5-(tert-butyl)-N-(2-(2-(2-((1,5-dimethyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl)-1,2,4-oxadiazole-3-carboxamide,-   (R)-5-(tert-butyl)-N-(2-(2-((1,5-dimethyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl)-1,2,4-oxadiazole-3-carboxamide,-   (S)-5-(tert-butyl)-N-(2-(2-((1,5-dimethyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl)-1,2,4-oxadiazole-3-carboxamide,-   5-(tert-butyl)-N-(2-(2-((5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)amino)pyrimidin-4-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl)-1,2,4-oxadiazole-3-carboxamide,-   (R)-5-(tert-butyl)-N-(2-(2-((5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)amino)pyrimidin-4-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl)-1,2,4-oxadiazole-3-carboxamide,-   (S)-5-(tert-butyl)-N-(2-(2-((5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)amino)pyrimidin-4-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl)-1,2,4-oxadiazole-3-carboxamide,-   5-(tert-butyl)-N-(2-(2-((1-methyl-5-(trifluoromethyl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl)-1,2,4-oxadiazole-3-carboxamide,-   (R)-5-(tert-butyl)-N-(2-(2-((1-methyl-5-(trifluoromethyl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl)-1,2,4-oxadiazole-3-carboxamide,-   (S)-5-(tert-butyl)-N-(2-(2-((1-methyl-5-(trifluoromethyl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl)-1,2,4-oxadiazole-3-carboxamide,-   1-(tert-butyl)-N-(2-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyridin-4-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl)-1H-1,2,3-triazole-4-carboxamide,-   (R)-1-(tert-butyl)-N-(2-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyridin-4-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl)-1H-1,2,3-triazole-4-carboxamide,-   (S)-1-(tert-butyl)-N-(2-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyridin-4-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl)-1H-1,2,3-triazole-4-carboxamide,-   N-(2-(2-hydroxyethyl)-8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-5-(1-methylcyclopropyl)-1,3,4-oxadiazole-2-carboxamide,-   (R)—N-(2-(2-hydroxyethyl)-8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-5-(1-methylcyclopropyl)-1,3,4-oxadiazole-2-carboxamide,    and-   (S)—N-(2-(2-hydroxyethyl)-8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-5-(1-methylcyclopropyl)-1,3,4-oxadiazole-2-carboxamide,-   or a pharmaceutically acceptable salt thereof.

The present invention also provides crystalline forms of(R)-1-(tert-butyl)-N-(8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(oxetan-3-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1H-1,2,3-triazole-4-carboxamide(compound 27):

As used herein, the term “crystalline” refers to a solid form having acrystal structure wherein the individual molecules have a highlyhomogeneous regular locked-in chemical configuration.

Form A

In one embodiment, the present invention provides crystalline Form A of(R)-1-(tert-butyl)-N-(8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(oxetan-3-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1H-1,2,3-triazole-4-carboxamide.

In one aspect, crystalline Form A is characterized by at least three, atleast four, or at least five powder X-ray diffraction (PXRD) peaks at 2θangles selected from 5.7°, 7.9°, 9.7°, 18.2°, 19.0° and 22.4°. In oneembodiment, crystalline Form A is characterized by powder X-raydiffraction peaks at 2θ angles selected from 5.7°, 7.9°, 9.7°, 18.2°,19.0° and 22.4°. In some embodiments, the peaks described above forcrystalline Form A have a relative intensity of at least 5%, at least10%, or at least 15%. In another embodiment, crystalline Form A ischaracterized by at least three, at least four, at least five, at leastsix, at least seven, at least eight, at least nine, at least ten, atleast eleven, at least twelve, at least thirteen, at least fourteen, atleast fifteen, at least sixteen, at least seventeen, or at leastnineteen PXRD peaks at 2θ angles selected from 4.3°, 5.7°, 7.9°, 8.7°,9.7°, 11.9°, 13.1°, 14.8°, 15.2°, 16.1°, 17.0°, 17.8°, 18.2°, 19.0°,20.5°, 21.2°, 22.4°, 22.8°, 23.8°, and 25.60.

As used herein, the term “relative intensity” refers to a ratio of thepeak intensity for the peak of interest versus the peak intensity forthe largest peak.

In another aspect, crystalline Form A has a PXRD pattern that issubstantially the same as PXRD pattern shown in FIG. 1.

In one aspect, crystalline Form A has a differential scanningcalorimetry (DSC) profile that is substantially the same as the DSCprofile shown in FIG. 2. In particular, crystalline Form A ischaracterized by an onset temperature at 175.6° C.±2° C. in the DSCprofile. In one embodiment, crystalline Form A has a melting temperatureof 186° C.±2° C.

In one aspect, crystalline Form A has a TGA profile that issubstantially the same as the TGA profile shown in FIG. 2. Inparticular, the TGA profile indicates that crystalline Form A is ahydrate.

As used herein, “hydrate” refers to refers to a crystalline solid adductcontaining(R)-1-(tert-butyl)-N-(8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(oxetan-3-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1H-1,2,3-triazole-4-carboxamideand either stoichiometric or nonstoichiometric amounts of a waterincorporated within the crystal structure. Techniques known in the artto determine the to determine the amount of water present include, forexample, TGA and Karl Fisher (KF) analysis.

In another aspect, crystalline Form A has a solid state ¹³C NMR spectrumthat is substantially the same as that shown in FIG. 3B. In oneembodiment, crystalline Form A is characterized by chemical shifts at143.7 ppm and/or 134.4 ppm in solid state ¹³C NMR spectrum. The spectrumof Form A exhibit broader signals without showing clear duplicatedsignals. The Form A spectrum also suggests that there may be twoindependent molecules with different geometry. In another embodiments,crystalline Form A is characterized by chemical shifts in solid state¹³C NMR spectrum as shown in Table 3.

In some embodiments, crystalline Form A is characterized by, forexample, PXRD, DSC, TGA or ¹³NMR described above or any combinationthereof. In one embodiment, crystalline Form A is characterized by PXRDalone or PXRD in combination with one or more of DSC, TGA and ¹³NMRdescribed above.

In some embodiments, crystalline Form A is at least 70%, 80%, 85%, 90%,95%, 97%, 99%, 99.5% or 99.9% pure. The purity of Form A is determinedby dividing the weight of crystalline Form A in a composition comprisingcompound(R)-1-(tert-butyl)-N-(8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(oxetan-3-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1H-1,2,3-triazole-4-carboxamideover the total weight of the compound in the composition. In oneembodiment, the present invention provides a composition comprisingcompound(R)-1-(tert-butyl)-N-(8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(oxetan-3-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1H-1,2,3-triazole-4-carboxamide,wherein at least 70%, 80%, 85%, 90%, 95%, 97%, 99%, 99.5% or 99.9% byweight of the compound in the composition is crystalline Form A of thecompound.

In one embodiment, the present invention provides a method for preparingcrystalline Form A of(R)-1-(tert-butyl)-N-(8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(oxetan-3-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1H-1,2,3-triazole-4-carboxamide.Such method includes, e.g., forming crystalline Form A from a slurrycomprising(R)-1-(tert-butyl)-N-(8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(oxetan-3-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1H-1,2,3-triazole-4-carboxamideand ethanol (EtOH). In one embodiment, the method comprises stirring theslurry containing(R)-1-(tert-butyl)-N-(8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(oxetan-3-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1H-1,2,3-triazole-4-carboxamideand EtOH at room temperature for 1 hour to 1 week, e.g., 1 hour, 2hours, 3 hours, 4 hours, 5 hours, 10 hours, 15 hours, 24 hours, or 48hours.

Form G

In one embodiment, the present invention provides crystalline Form G of(R)-1-(tert-butyl)-N-(8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(oxetan-3-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1H-1,2,3-triazole-4-carboxamide.

In one aspect, crystalline Form G is characterized by at least three, atleast four or at least five PXRD peaks at 2θ angles selected from 3.6°,8.9°, 10.9°, 12.6°, 20.2° and 21.8°. In one embodiment, crystalline FormG is characterized by PXRD peaks at 2θ angles selected from 3.6°, 8.9°,10.9°, 12.6°, 20.2° and 21.8°. In some embodiments, the peaks describedabove for crystalline Form G have a relative intensity of at least 5%,at least 10%, or at least 15%. In another embodiment, crystalline Form Gis characterized by at least three, at least four, at least five, atleast six, at least seven, at least eight, at least nine, at least ten,at least eleven, at least twelve, or at least thirteen PXRD peaks at 2θangles selected from 3.6°, 8.9°, 11.0°, 12.6°, 14.5°, 15.4°, 16.3°,18.4°, 20.2°, 21.8°, 23.4°, 25.4°, 26.8°, and 34.2°. In anotherembodiment, crystalline Form A is characterized by PXRD peaks at 2θangles selected from 3.6°, 8.9°, 11.0°, 12.6°, 14.5°, 15.4°, 16.3°,18.4°, 20.2°, 21.8°, 23.4°, 25.4°, 26.8°, and 34.2°.

In another aspect, crystalline Form G has a PXRD pattern that issubstantially the same as PXRD pattern shown in FIG. 4.

In one aspect, crystalline Form G has a DSC profile that issubstantially the same as the DSC profile shown in FIG. 5. Inparticular, crystalline Form G is characterized by an onset temperatureat 215.4° C.±2° C. in the DSC profile. In another embodiment,crystalline Form G has a melting temperature of 217° C.±2° C.

In one aspect, crystalline Form G has a TGA profile that issubstantially the same as the TGA profile shown in FIG. 5. Inparticular, the TGA profile indicates that crystalline Form G is ananhydrate.

“Anhydrate” as used herein, means that the crystalline form comprisessubstantially no water in the crystal lattice e.g., less than 1% byweight as determined by, for example, TGA analysis or other quantitativeanalysis.

In another aspect, crystalline Form G has a solid state ¹³C NMR spectrumthat is substantially the same as that shown in FIG. 6B. In oneembodiment, crystalline Form G is characterized by chemical shifts at147.0 ppm, 146.0 ppm and/or 140.6 ppm in solid state ¹³C NMR spectrum.The spectrum of Form G shows peak splitting (duplicate signals) inaromatic regions when compared to the solution ¹³C NMR spectrumsuggesting there are two independent molecules in the asymmetric unit.In another embodiment, crystalline Form G is characterized by chemicalshifts in solid state ¹³C NMR spectrum as shown in Table 3.

In some embodiments, crystalline Form G is at least 70%, 80%, 85%, 90%,95%, 97%, 99%, 99.5% or 99.9% pure. The purity of Form G is determinedby dividing the weight of crystalline Form G in a composition comprisingcompound(R)-1-(tert-butyl)-N-(8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(oxetan-3-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1H-1,2,3-triazole-4-carboxamideover the total weight of the compound in the composition. In oneembodiment, the present invention provides a composition comprisingcompound(R)-1-(tert-butyl)-N-(8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(oxetan-3-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1H-1,2,3-triazole-4-carboxamide,wherein at least 70%, 80%, 85%, 90%, 95%, 97%, 99%, 99.5% or 99.9% byweight of the compound in the composition is crystalline Form G of thecompound.

In one embodiment, the present invention provides a method for preparingcrystalline Form G of(R)-1-(tert-butyl)-N-(8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(oxetan-3-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1H-1,2,3-triazole-4-carboxamide.Such method includes, e.g., forming crystalline Form G from a slurrycomprising(R)-1-(tert-butyl)-N-(8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(oxetan-3-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1H-1,2,3-triazole-4-carboxamideand isopropyl acetate (IPAc). In one embodiment, the method comprisesstirring the slurry containing(R)-1-(tert-butyl)-N-(8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(oxetan-3-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1H-1,2,3-triazole-4-carboxamideand isopropyl acetate (IPAc) at an elevated temperature (e.g., between30° C. and 70° C., between 40° C. and 60° C., between 45° C. and 55° C.,or at 50° C.), for 1 hour to 1 week, e.g., 1 hour, 2 hours, 3 hours, 4hours, 5 hours, 10 hours, 15 hours, 24 hours, or 48 hours.

Alternatively, crystalline Form G can be prepared by a method comprisingthe steps of (i) removing at least a portion of dichloromethane bydistillation from a mixture containing(R)-1-(tert-butyl)-N-(8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(oxetan-3-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1H-1,2,3-triazole-4-carboxamideand dichloromethane; (ii) adding isopropyl acetate (IPAc) to themixture; (iii) heating the mixture containing IPAc to an elevatedtemperature (e.g., between 50° C. and 70° C., between 55° C. and and 65°C. or 60° C.) followed by cooling to near room temperature (e.g., 20°C.) to form a slurry containing the compound and IPAc; and (iv)isolating crystalline Form G from the slurry. In one embodiment, steps(i) and (ii) can be repeated for one or more times (e.g. two, three,four, or five times). In one embodiment, steps (i) and (ii) are repeateduntil substantially all (e.g., at least 60%, at least 70%, at least 80%,at least 90%, or at least 95% by volume) of dichloromethane is removed.In one embodiment, the heating and the cooling in step (iii) can berepeated for one or more times (e.g. two, three, four, five, ten,fifteen, twenty, or more times).

It will be understood that the 2θ values of the PXRD pattern forcrystalline Form A or crystalline Form G may vary slightly from oneinstrument to another and may depend on variations in samplepreparation. Therefore, the PXRD peak positions for crystalline Form Aor crystalline Form G are not to be construed as absolute and can vary±0.2°.

As intended herein, “substantially the same PXRD pattern as shown inFIG. 1”, “substantially the same PXRD pattern as shown in FIG. 4”,“substantially the same as that shown in FIG. 3B” or “substantially thesame as that shown in FIG. 6B” mean that for comparison purposes, atleast 80%, at least 90%, or at least 95% of the peaks shown in FIG. 1,FIG. 4, FIG. 3B and FIG. 6B are present. It is to be further understoodthat for comparison purposes some variability in peak position fromthose shown in FIG. 1 and FIG. 4 are allowed, such as ±0.2°. Similarly,for comparison purposes some variability in peak position from thoseshown in FIG. 3B and FIG. 6B are allowed, such as ±0.5 ppm.

As used herein, the term “alkyl” refers to a fully saturated branched orunbranched hydrocarbon moiety. Preferably the alkyl comprises 1 to 6carbon atoms, or 1 to 4 carbon atoms. In some embodiments, an alkylcomprises from 6 to 20 carbon atoms. Representative examples of alkylinclude, but are not limited to, methyl, ethyl, n-propyl, iso-propyl,n-butyl, sec-butyl, iso-butyl, tert-butyl, n-pentyl, isopentyl,neopentyl, or n-hexyl.

“Alkenyl” refers to an unsaturated hydrocarbon group which may be linearor branched and has at least one carbon-carbon double bond. Alkenylgroups with 2-6 carbon atoms can be preferred. The alkenyl group maycontain 1, 2 or 3 carbon-carbon double bonds, or more. Examples ofalkenyl groups include ethenyl, n-propenyl, iso-propenyl, n-but-2-enyl,n-hex-3-enyl and the like.

“Alkynyl” refers to an unsaturated hydrocarbon group which may be linearor branched and has at least one carbon-carbon triple bond. Alkynylgroups with 2-6 carbon atoms can be preferred.

The alkynyl group may contain 1, 2 or 3 carbon-carbon triple bonds, ormore. Examples of alkynyl groups include ethynyl, n-propynyl,n-but-2-ynyl, n-hex-3-ynyl and the like.

The number of carbon atoms in a group is specified herein by the prefix“C_(x-xx)”, wherein x and xx are integers. For example, “C₁₋₄alkyl” isan alkyl group which has from 1 to 4 carbon atoms.

“Halogen” or “halo” may be fluoro, chloro, bromo or iodo.

As used herein, the term “heterocyclyl” refers to a saturated orunsaturated, monocyclic or bicyclic (e.g., fused, bridged or spiro ringsystems) ring system which has from 3- to 10-ring members, or inparticular 3- to 8-ring members, 3- to 7-ring members, 3- to 6-ringmembers or 5- to 7-ring members or 4- to 7-ring members, at least one ofwhich is a heteroatom, and up to 4 (e.g., 1, 2, 3, or 4) of which may beheteroatoms, wherein the heteroatoms are independently selected from O,S and N, and wherein C can be oxidized (e.g., C(O)), N can be oxidized(e.g., N(O)) or quaternized, and S can be optionally oxidized tosulfoxide and sulfone. Unsaturated heterocyclic rings include heteroarylrings. As used herein, the term “heteroaryl” refers to an aromatic 5- or6-membered monocyclic ring system, having 1 to 4 heteroatomsindependently selected from O, S and N, and wherein N can be oxidized(e.g., N(O)) or quaternized, and S can be optionally oxidized tosulfoxide and sulfone. In one embodiment, a heterocyclyl is a 3- to7-membered saturated monocyclic or a 3- to 6-membered saturatedmonocyclic or a 5- to 7-membered saturated monocyclic ring or a 4- to6-membered saturated monocyclic ring. In one embodiment, a heterocyclylis a 3- to 7-membered monocyclic or a 3- to 6-membered monocyclic or a4- to 6-membered monocyclic ring or a 5- to 7-membered monocyclic ring.In another embodiment, a heterocyclyl is a 6 or-7-membered bicyclicring. In yet another embodiment, a heterocyclyl is a 4- to 7-memberedmonocyclic non-aromatic ring. In another embodiment, a heterocyclyl is6- to 8-membered spiro or bridged bicyclic ring. The heterocyclyl groupcan be attached at a heteroatom or a carbon atom. Examples ofheterocyclyls include, but are not limited to, aziridinyl, oxiranyl,thiiranyl, oxaziridinyl, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl,tetrahydrofuranyl, thiolanyl, imidazolidinyl, pyrazolidinyl,oxazolidinyl, isoxazolidinyl, thiazolidinyl, isothiazolidinyl,dioxolanyl, dithiolanyl, oxathiolanyl, piperidinyl, tetrahydropyranyl,thianyl, piperazinyl, morpholinyl, thiomorpholinyl, dioxanyl, dithianyl,trioxanyl, trithianyl, azepanyl, oxepanyl, thiepanyl, dihydrofuranyl,imidazolinyl, dihydropyranyl, and heteroaryl rings including azetyl,thietyl, pyrrolyl, furanyl, thiophenyl (or thienyl), imidazolyl,pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, furazanyl,oxadiazolyl, thiadiazolyl, dithiazolyl, triazolyl, tetrazolyl,pyridinyl, pyranyl, thiopyranyl, pyrazinyl, pyrimidinyl, pyridazinyl,oxazinyl, thiazinyl, dioxinyl, dithiinyl, oxathianyl, triazinyl,tetrazinyl, azepinyl, oxepinyl, thiepinyl, diazepinyl, and thiazepinyland the like.

The term “fused ring system”, as used herein, is a ring system that hastwo rings each of which are independently selected from a carbocyclyl ora heterocyclyl, wherein the two ring structures share two adjacent ringatoms. A fused ring system may have from 9 to 12 ring members.

The term “bridged ring system”, as used herein, is a ring system thathas a carbocyclyl or heterocyclyl ring wherein two non-adjacent atoms ofthe ring are connected (bridged) by one or more (preferably from one tothree) atoms selected from C, N, O, or S. A bridged ring system may havefrom 6 to 8 ring members.

The term “spiro ring system,” as used herein, is a ring system that hastwo rings each of which are independently selected from a carbocyclyl ora heterocyclyl, wherein the two ring structures having one ring atom incommon. Spiro ring systems have from 5 to 8 ring members.

In one embodiment, a heterocyclyl is a 4- to 6-membered monocyclicheterocyclyl. Examples of 4- to 6-membered monocyclic heterocyclic ringsystems include, but are not limited to azetidinyl, pyrrolidinyl,tetrahydrofuranyl, thiolanyl, imidazolidinyl, pyrazolidinyl,oxazolidinyl, isoxazolidinyl, thiazolidinyl, isothiazolidinyl,dioxolanyl, dithiolanyl, oxathiolanyl, piperidinyl, tetrahydropyranyl,thianyl, piperazinyl, morpholinyl, thiomorpholinyl, dioxanyl, dithianyl,dihydrofuranyl, imidazolinyl, dihydropyranyl, pyrrolyl, furanyl,thiophenyl (or thienyl), imidazolyl, pyrazolyl, oxazolyl, isoxazolyl,thiazolyl, isothiazolyl, furazanyl, oxadiazolyl, thiadiazolyl,dithiazolyl, triazolyl, tetrazolyl, pyridinyl, pyranyl, thiopyranyl,pyrazinyl, pyrimidinyl, pyridazinyl, oxazinyl, thiazinyl, dioxinyl,dithiinyl, oxathianyl, triazinyl, and tetrazinyl.

In another embodiment, a heterocyclyl is a saturated 4- to 6-memberedmonocyclic heterocyclyl. Examples of saturated 4- to 6-memberedmonocyclic heterocyclic ring systems include, but are not limited toazetidinyl, pyrrolidinyl, tetrahydrofuranyl, thiolanyl, imidazolidinyl,pyrazolidinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl,isothiazolidinyl, dioxolanyl, dithiolanyl, oxathiolanyl, piperidinyl,tetrahydropyranyl, thianyl, piperazinyl, morpholinyl, thiomorpholinyl,dioxanyl, and dithiinyl. In one embodiment, a saturated 4- to 6-memberedmonocyclic heterocyclyl is azetidinyl, oxetanyl, pyrrolidinyl,tetrahydrofuranyl, thiolanyl, imidazolidinyl, pyrazolidinyl,oxazolidinyl, isoxazolidinyl, thiazolidinyl, isothiazolidinyl,dioxolanyl, dithiolanyl, oxathiolanyl, piperidinyl, tetrahydropyranyl,thianyl, piperazinyl, morpholinyl, thiomorpholinyl, or dioxinyl. Inanother embodiment, a saturated 4- to 6-membered monocyclic heterocyclylis oxetanyl, tetrahydrofuranyl, or tetrahydropyranyl.

As used herein, the term “carbocyclyl” refers to saturated orunsaturated monocyclic or bicyclic hydrocarbon groups of 3-7 carbonatoms, 3-5, 3-6, 4-6, or 5-7 carbon atoms. The term “carbocyclyl”encompasses cycloalkyl groups and aromatic groups. The term “cycloalkyl”refers to completely saturated monocyclic or bicyclic or spirohydrocarbon groups of 3-7 carbon atoms, 3-6 carbon atoms, or 5-7 carbonatoms. Exemplary monocyclic carbocyclyl groups include, but are notlimited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,cycloheptyl, cyclopropenyl, cyclobutenyl, cyclopenentyl, cyclohexenyl,cycloheptenyl, cyclobutadienyl, cyclopentadienyl, cyclohexadienyl,cycloheptadienyl, phenyl and cycloheptatrienyl. Exemplary bicycliccarbocyclyl groups include bicyclo[2.1.1]hexyl, bicyclo[2.2.1]heptyl,bicyclo[2.2.1]heptenyl, tricyclo[2.2.1.0^(2,6)]heptanyl,6,6-dimethylbicyclo[3.1.1]heptyl, or2,6,6-trimethylbicyclo[3.1.1]heptyl, spiro[2.2]pentanyl, andspiro[3.3]heptanyl. In one embodiment, the carbocyclyl is a 4- to6-membered monocyclic carbocyclyl. In another embodiment, thecarbocyclyl is a 3- to 5-membered carbocyclyl. In one embodiment, thecarbocyclyl is a C₄₋₆ cycloalkyl. In yet another embodiment, thecarbocyclyl is cyclobutyl, cyclopentyl or cyclohexyl.

In cases where a compound provided herein is sufficiently basic oracidic to form stable nontoxic acid or base salts, preparation andadministration of the compounds as pharmaceutically acceptable salts maybe appropriate. Examples of pharmaceutically acceptable salts areorganic acid addition salts formed with acids which form a physiologicalacceptable anion, for example, tosylate, methanesulfonate, acetate,citrate, malonate, tartarate, succinate, benzoate, ascorbate,α-ketoglutarate, or α-glycerophosphate. Inorganic salts may also beformed, including hydrochloride, sulfate, nitrate, bicarbonate, andcarbonate salts.

Pharmaceutically acceptable salts may be obtained using standardprocedures well known in the art, for example by reacting a sufficientlybasic compound such as an amine with a suitable acid affording aphysiologically acceptable anion. Alkali metal (for example, sodium,potassium or lithium) or alkaline earth metal (for example calcium)salts of carboxylic acids can also be made.

Pharmaceutically-acceptable base addition salts can be prepared frominorganic and organic bases. Salts from inorganic bases, can include butare not limited to, sodium, potassium, lithium, ammonium, calcium ormagnesium salts. Salts derived from organic bases can include, but arenot limited to, salts of primary, secondary or tertiary amines, such asalkyl amines, dialkyl amines, trialkyl amines, substituted alkyl amines,di(substituted alkyl) amines, tri(substituted alkyl) amines, alkenylamines, dialkenyl amines, trialkenyl amines, substituted alkenyl amines,di(substituted alkenyl) amines, tri(substituted alkenyl) amines,cycloalkyl amines, di(cycloalkyl) amines, tri(cycloalkyl) amines,substituted cycloalkyl amines, disubstituted cycloalkyl amine,trisubstituted cycloalkyl amines, cycloalkenyl amines, di(cycloalkenyl)amines, tri(cycloalkenyl) amines, substituted cycloalkenyl amines,disubstituted cycloalkenyl amine, trisubstituted cycloalkenyl amines,aryl amines, diaryl amines, triaryl amines, heteroaryl amines,diheteroaryl amines, triheteroaryl amines, heterocycloalkyl amines,diheterocycloalkyl amines, triheterocycloalkyl amines, or mixed di- andtri-amines where at least two of the substituents on the amine can bedifferent and can be alkyl, substituted alkyl, alkenyl, substitutedalkenyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substitutedcycloalkenyl, aryl, heteroaryl, or heterocycloalkyl and the like. Alsoincluded are amines where the two or three substituents, together withthe amino nitrogen, form a heterocycloalkyl or heteroaryl group.Non-limiting examples of amines can include, isopropylamine, trimethylamine, diethyl amine, tri(iso-propyl) amine, tri(n-propyl) amine,ethanolamine, 2-dimethylaminoethanol, trimethamine, lysine, arginine,histidine, caffeine, procaine, hydrabamine, choline, betaine,ethylenediamine, glucosamine, N-alkylglucamines, theobromine, purines,piperazine, piperidine, morpholine, or N-ethylpiperidine, and the like.Other carboxylic acid derivatives can be useful, for example, carboxylicacid amides, including carboxamides, lower alkyl carboxamides, ordialkyl carboxamides, and the like.

The compounds or pharmaceutically acceptable salts thereof as describedherein, can contain one or more asymmetric centers in the molecule. Inaccordance with the present disclosure any structure that does notdesignate the stereochemistry is to be understood as embracing all thevarious stereoisomers (e.g., diastereomers and enantiomers) in pure orsubstantially pure form, as well as mixtures thereof (such as a racemicmixture, or an enantiomerically enriched mixture). It is well known inthe art how to prepare such optically active forms (for example,resolution of the racemic form by recrystallization techniques,synthesis from optically-active starting materials, by chiral synthesis,or chromatographic separation using a chiral stationary phase).

When a particular stereoisomer of a compound is depicted by name orstructure, the stereochemical purity of the compounds is at least 20%,30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 97%, 99%, 99.5% or 99.9%.“Stereochemical purity” means the weight percent of the desiredstereoisomer relative to the combined weight of all stereoisomers.

When a particular enantiomer of a compound is depicted by name orstructure, the stereochemical purity of the compounds is at least 20%,30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 97%, 99%, 99.5% or 99.9%.“Stereochemical purity” means the weight percent of the desiredenantiomer relative to the combined weight of all stereoisomers.

When the stereochemistry of a disclosed compound is named or depicted bystructure, and the named or depicted structure encompasses more than onestereoisomer (e.g., as in a diastereomeric pair), it is to be understoodthat one of the encompassed stereoisomers or any mixture of theencompassed stereoisomers are included. It is to be further understoodthat the stereoisomeric purity of the named or depicted stereoisomers atleast 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 97%, 99%, 99.5% or99.9%. The stereoisomeric purity the weight percent of the desiredstereoisomers encompassed by the name or structure relative to thecombined weight of all of the stereoisomers.

When a disclosed compound is named or depicted by structure withoutindicating the stereochemistry, and the compound has one chiral center,it is to be understood that the name or structure encompasses oneenantiomer of compound in pure or substantially pure form, as well asmixtures thereof (such as a racemic mixture of the compound and mixturesenriched in one enantiomer relative to its corresponding opticalisomer).

When a disclosed compound is named or depicted by structure withoutindicating the stereochemistry and, e.g., the compound has at least twochiral centers, it is to be understood that the name or structureencompasses one stereoisomer in pure or substantially pure form, as wellas mixtures thereof (such as mixtures of stereoisomers, and mixtures ofstereoisomers in which one or more stereoisomers is enriched relative tothe other stereoisomer(s)).

The disclosed compounds may exist in tautomeric forms and mixtures andseparate individual tautomers are contemplated. In addition, somecompounds may exhibit polymorphism.

In one embodiment, the compounds of the invention or a pharmaceuticallyacceptable salt thereof include deuterium.

Another embodiment is a pharmaceutical composition comprising at leastone compound described herein, or a pharmaceutically acceptable saltthereof, and at least one pharmaceutically acceptable carrier.

The compounds, or pharmaceutically acceptable salts thereof describedherein may be used to decrease the activity of Btk, or to otherwiseaffect the properties and/or behavior of Btk, e.g., stability,phosphorylation, kinase activity, interactions with other proteins, etc.

In some embodiments, the present invention provides methods ofdecreasing Btk enzymatic activity. In some embodiments, such methodsinclude contacting a Btk with an effective amount of a Btk inhibitor.Therefore, the present invention further provides methods of inhibitingBtk enzymatic activity by contacting a Btk with a Btk inhibitor of thepresent invention.

One embodiment of the invention includes a method of treating a disorderresponsive to inhibition of Btk in a subject comprising administering tosaid subject an effective amount of at least one compound describedherein, or a pharmaceutically acceptable salt thereof.

In one embodiment, the present invention provides methods of treatingautoimmune disorders, inflammatory disorders, and cancers in a subjectin need thereof comprising administering to said subject an effectiveamount of at least one compound described herein, or a pharmaceuticallyacceptable salt thereof.

The term “autoimmune disorders” includes diseases or disorders involvinginappropriate immune response against native antigens, such as acutedisseminated encephalomyelitis (ADEM), Addison's disease, alopeciaareata, antiphospholipid antibody syndrome (APS), autoimmune hemolyticanemia, autoimmune hepatitis, bullous pemphigoid (BP), Coeliac disease,dermatomyositis, diabetes mellitus type 1, Goodpasture's syndrome,Graves' disease, Guillain-Barre syndrome (GBS), Hashimoto's disease,idiopathic thrombocytopenic purpura, lupus erythematosus, mixedconnective tissue disease, multiple sclerosis, myasthenia gravis,pemphigus vulgaris, pernicious anaemia, polymyositis, primary biliarycirrhosis, Sjogren's syndrome, temporal arteritis, and Wegener'sgranulomatosis. The term “inflammatory disorders” includes diseases ordisorders involving acute or chronic inflammation such as allergies,asthma, prostatitis, glomerulonephritis, pelvic inflammatory disease(PID), inflammatory bowel disease (IBD, e.g., Crohn's disease,ulcerative colitis), reperfusion injury, rheumatoid arthritis,transplant rejection, and vasculitis. In some embodiments, the presentinvention provides a method of treating rheumatoid arthritis or lupus.In some embodiments, the present invention provides a method of treatingmultiple sclerosis.

The term “cancer” includes diseases or disorders involving abnormal cellgrowth and/or proliferation, such as glioma, thyroid carcinoma, breastcarcinoma, lung cancer (e.g. small-cell lung carcinoma, non-small-celllung carcinoma), gastric carcinoma, gastrointestinal stromal tumors,pancreatic carcinoma, bile duct carcinoma, ovarian carcinoma,endometrial carcinoma, prostate carcinoma, renal cell carcinoma,lymphoma (e.g., anaplastic large-cell lymphoma), leukemia (e.g. acutemyeloid leukemia, T-cell leukemia, chronic lymphocytic leukemia),multiple myeloma, malignant mesothelioma, malignant melanoma, and coloncancer (e.g. microsatellite instability-high colorectal cancer). In someembodiments, the present invention provides a method of treatingleukemia or lymphoma.

As used herein, the term “subject” and “patient” may be usedinterchangeably, and means a mammal in need of treatment, e.g.,companion animals (e.g., dogs, cats, and the like), farm animals (e.g.,cows, pigs, horses, sheep, goats and the like) and laboratory animals(e.g., rats, mice, guinea pigs and the like). Typically, the subject isa human in need of treatment.

As used herein, the term “treating” or ‘treatment” refers to obtainingdesired pharmacological and/or physiological effect. The effect can betherapeutic, which includes achieving, partially or substantially, oneor more of the following results: partially or totally reducing theextent of the disease, disorder or syndrome; ameliorating or improving aclinical symptom or indicator associated with the disorder; or delaying,inhibiting or decreasing the likelihood of the progression of thedisease, disorder or syndrome.

The effective dose of a compound provided herein, or a pharmaceuticallyacceptable salt thereof, administered to a subject can be 10 μg-500 mg.

Administering a compound described herein, or a pharmaceuticallyacceptable salt thereof, to a mammal comprises any suitable deliverymethod. Administering a compound described herein, or a pharmaceuticallyacceptable salt thereof, to a mammal includes administering a compounddescribed herein, or a pharmaceutically acceptable salt thereof,topically, enterally, parenterally, transdermally, transmucosally, viainhalation, intracisternally, epidurally, intravaginally, intravenously,intramuscularly, subcutaneously, intradermally or intravitreally to themammal.

Administering a compound described herein, or a pharmaceuticallyacceptable salt thereof, to a mammal also includes administeringtopically, enterally, parenterally, transdermally, transmucosally, viainhalation, intracisternally, epidurally, intravaginally, intravenously,intramuscularly, subcutaneously, intradermally or intravitreally to amammal a compound that metabolizes within or on a surface of the body ofthe mammal to a compound described herein, or a pharmaceuticallyacceptable salt thereof.

Thus, a compound or pharmaceutically acceptable salt thereof asdescribed herein, may be systemically administered, e.g., orally, incombination with a pharmaceutically acceptable vehicle such as an inertdiluent or an assimilable edible carrier. They may be enclosed in hardor soft shell gelatin capsules, may be compressed into tablets, or maybe incorporated directly with the food of the patient's diet. For oraltherapeutic administration, the compound or pharmaceutically acceptablesalt thereof as described herein may be combined with one or moreexcipients and used in the form of ingestible tablets, buccal tablets,troches, capsules, elixirs, suspensions, syrups, or wafers, and thelike. Such compositions and preparations should contain at least about0.1% of active compound.

The percentage of the compositions and preparations may, of course, bevaried and may conveniently be between about 2 to about 60% of theweight of a given unit dosage form. The amount of active compound insuch therapeutically useful compositions can be such that an effectivedosage level will be obtained.

The tablets, troches, pills, capsules, and the like can include thefollowing: binders such as gum tragacanth, acacia, corn starch orgelatin; excipients such as dicalcium phosphate; a disintegrating agentsuch as corn starch, potato starch, alginic acid and the like; alubricant such as magnesium stearate; or a sweetening agent such assucrose, fructose, lactose or aspartame or a flavoring agent.

The active compound may also be administered intravenously orintraperitoneally by infusion or injection. Solutions of the activecompound or its salts can be prepared in water, optionally mixed with anontoxic surfactant.

Exemplary pharmaceutical dosage forms for injection or infusion caninclude sterile aqueous solutions or dispersions or sterile powderscomprising the active ingredient which are adapted for theextemporaneous preparation of sterile injectable or infusible solutionsor dispersions. In all cases, the ultimate dosage form should besterile, fluid and stable under the conditions of manufacture andstorage.

Sterile injectable solutions can be prepared by incorporating the activecompound in the required amount in the appropriate solvent with variousof the other ingredients enumerated above, as required, followed byfilter sterilization. In the case of sterile powders for the preparationof sterile injectable solutions, the preferred methods of preparationcan be vacuum drying and the freeze drying techniques, which can yield apowder of the active ingredient plus any additional desired ingredientpresent in the previously sterile-filtered solutions.

Exemplary solid carriers can include finely divided solids such as talc,clay, microcrystalline cellulose, silica, alumina and the like. Usefulliquid carriers include water, alcohols or glycols orwater-alcohol/glycol blends, in which the compounds or pharmaceuticallyacceptable salts thereof as described herein can be dissolved ordispersed at effective levels, optionally with the aid of nontoxicsurfactants.

Useful dosages of a compound or pharmaceutically acceptable salt thereofas described herein can be determined by comparing their in vitroactivity, and in vivo activity in animal models.

Methods for the extrapolation of effective dosages in mice, and otheranimals, to humans are known to the art; for example, see U.S. Pat. No.4,938,949, which is incorporated by reference in its entirety.

The amount of a compound or pharmaceutically acceptable salt thereof asdescribed herein, required for use in treatment can vary not only withthe particular salt selected but also with the route of administration,the nature of the condition being treated and the age and condition ofthe patient and can be ultimately at the discretion of the attendantphysician or clinician. In general, however, a dose can be in the rangeof from about 0.1 to about 10 mg/kg of body weight per day.

The a compound or pharmaceutically acceptable salt thereof as describedherein can be conveniently administered in unit dosage form; forexample, containing 0.01 to 10 mg, or 0.05 to 1 mg, of active ingredientper unit dosage form. In some embodiments, a dose of 5 mg/kg or less canbe suitable.

The desired dose may conveniently be presented in a single dose or asdivided doses administered at appropriate intervals.

The disclosed method can include a kit comprising a compound orpharmaceutically acceptable salt thereof as described herein andinstructional material which can describe administering a compound orpharmaceutically acceptable salt thereof as described herein or acomposition comprising a compound or pharmaceutically acceptable saltthereof as described herein to a cell or a subject. This should beconstrued to include other embodiments of kits that are known to thoseskilled in the art, such as a kit comprising a (such as sterile) solventfor dissolving or suspending a compound or pharmaceutically acceptablesalt thereof as described herein or composition prior to administering acompound or pharmaceutically acceptable salt thereof as described hereinor composition to a cell or a subject. In some embodiments, the subjectcan be a human.

EXEMPLIFICATIONS

LCMS methods: Samples were analyzed on a Waters Acquity UPLC BEH C18 1.7uM 2.1×50 mm, part number 186002350 machine, MS mode: MS:ESI+ scan range100-1000 daltons. PDA detection 210-400 nm. The method utilized was 95%water/5% MeCN (initial conditions) linear gradient to 5% H₂O/95% MeCN at1 min, HOLD 5% H₂O/95% MeCN to 1.3 min at 0.7 ml/min in 0.1%trifluoroacetic acid (0.1% v/v) and the injection volume was 0.5 uL.

SFC separations: Each separation was run with conditions as specified inthe examples below, including column name/part number, separationmethod, backpressure regulator setting on the SFC system, flowrate,detection wavelength, injection volume, sample concentration, and samplediluent.

Example 1:5-(tert-butyl)-N-(7-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-1-yl)-1,2,4-oxadiazole-3-carboxamide

1. Synthesis of N-(3-bromophenethyl)-4-methylbenzenesulfonamide

To a mixture of 2-(3-bromophenyl)ethanamine (2 g, 10 mmol) in CH₂Cl₂ (10mL), triethylamine (2.02 g, 20 mmol) and TsCl (2.18 g, 11.5 mmol) wereadded at 0° C. The mixture was stirred at rt for 2 h, diluted with NaOH(1N, 100 mL) and extracted with CH₂Cl₂ (100 mL). The organic layer waswashed with water (100 mL), brine (100 mL), dried (Na₂SO₄) andconcentrated in vacuo to giveN-(3-bromophenethyl)-4-methylbenzenesulfonamide (3.5 g, yield: 100%) asa yellow oil. ESI-MS (M+H)⁺: 354.0. ¹H NMR (400 MHz, CDCl₃) δ: 7.69 (d,J=8.0 Hz, 2H), 7.34 (d, J=8.4 Hz, 1H), 7.30 (d, J=8.0 Hz, 2H), 7.17 (t,J=1.6 Hz, 1H), 7.13 (t, J=8.0 Hz, 1H), 7.03-7.02 (m, 1H), 4.52 (t, J=6.0Hz, 1H), 3.22-3.17 (m, 2H), 2.73 (t, J=6.8 Hz, 2H), 2.45 (s, 3H).

2. Synthesis of ethyl2-(N-(3-bromophenethyl)-4-methylphenylsulfonamido)acetate

To a mixture of N-(3-bromophenethyl)-4-methylbenzenesulfonamide (7.2 g,20 mmol) in (CH₃)₂CO (80 mL), K₂CO₃ (19.3 g, 140 mmol) and ethyl2-bromoacetate (3.67 g, 22 mmol) were added. The mixture was stirred at60° C. for 12 h, cooled to rt and the salt was filtered out. Theresulting filtrate was concentrated in vacuo to give ethyl2-(N-(3-bromophenethyl)-4-methylphenylsulfonamido)acetate (8.78 g,yield: 100%) as a yellow oil. ESI-MS (M+H)⁺: 440.0. ¹H NMR (400 MHz,CDCl₃) δ: 7.70 (d, J=8.4 Hz, 2H), 7.34 (d, J=8.4 Hz, 1H), 7.28 (d, J=8.0Hz, 2H), 7.14 (t, J=7.6 Hz, 1H), 7.10-7.08 (m, 2H), 4.08 (q, J=7.6 Hz,2H), 3.98 (s, 2H), 3.44 (t, J=7.6 Hz, 2H), 2.85 (t, J=7.2 Hz, 2H), 2.42(s, 3H), 1.19 (t, J=7.2 Hz, 3H).

3. Synthesis of 2-(N-(3-bromophenethyl)-4-methylphenylsulfonamido)aceticacid

To a solution of ethyl2-(N-(3-bromophenethyl)-4-methylphenylsulfonamido)acetate (8.78 mg, 20mmol) in EtOH (40 mL) and H₂O (40 mL) was added NaOH (1.6 g, 40 mmol).The reaction mixture was stirred at rt for 12 h. Then the solvent wasreduced and the residue was adjusted to pH=3 with HCl (1 N). The mixturewas extracted with EtOAc (100 mL×3). The organic layers were dried over(Na₂SO₄) and concentrated in vacuo to give2-(N-(3-bromophenethyl)-4-methylphenylsulfonamido)acetic acid as ayellow solid (8.2 g, yield: 100%). ESI-MS (M+H)⁺: 412.0. ¹H NMR (400MHz, CDCl₃) δ: 7.69 (d, J=8.0 Hz, 2H), 7.34 (d, J=7.6 Hz, 1H), 7.29 (d,J=8.4 Hz, 2H), 7.22 (s, 1H), 7.14 (t, J=8.0 Hz, 1H), 7.08-7.06 (m, 1H),4.00 (s, 2H), 3.45 (t, J=7.6 Hz, 2H), 2.83 (t, J=7.6 Hz, 2H), 2.42 (s,3H).

4. Synthesis of7-bromo-3-tosyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-1-one

To a solution of2-(N-(3-bromophenethyl)-4-methylphenylsulfonamido)acetic acid (8.2 g, 20mmol) in CH₂Cl₂ (100 mL) was added SOCl₂ (11.9 g, 100 mmol) and DMF(cat.). The reaction mixture was stirred at 40° C. for 1 h. Then thesolvent was removed under reduced pressure and dried in vacuo for 2 h.The residue was dissolved in CH₂Cl₂ (100 mL) and cooled in an ice bath.AlCl₃ (10.56 g, 80 mmol) was added and the mixture was stirred at 0°C.-rt for 12 h. The mixture was poured into conc. HCl (20 mL) andextracted with EtOAc (100 mL×2). The organic layers were washed withwater (100 mL), brine (100 mL), dried (Na₂SO₄), and concentrated invacuo to afford a residue which was purified by silica gel column(petroleum ether:EtOAc=4:1) to give7-bromo-3-tosyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-1-one as a yellowsolid (1.88 g, yield: 24%). ESI-MS (M+H)⁺: 394.1. ¹H NMR (400 MHz,CDCl₃) δ: 7.42 (d, J=8.4 Hz, 2H), 7.38 (dd, J=8.4, 1.6 Hz, 1H),7.31-7.29 (m, 2H), 7.14 (d, J=8.0 Hz, 2H), 4.21 (s, 2H), 3.68 (t, J=6.8Hz, 2H), 2.93 (t, J=7.2 Hz, 2H), 2.39 (s, 3H).

5. Synthesis of7-bromo-3-tosyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-1-amine

Synthesis of7-bromo-3-tosyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-1-amine was similarto that of Example 2. The residue was purified by silica gel column(CH₂Cl₂:MeOH=20:1) to give7-bromo-3-tosyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-1-amine as a yellowsolid (154 mg, yield: 64%). ESI-MS (M+H)⁺: 395.1. ¹H NMR (400 MHz,CDCl₃) δ: 7.66 (d, J=8.4 Hz, 2H), 7.37 (d, J=8.4 Hz, 2H), 7.31 (dd,J=8.4, 1.6 Hz, 1H), 7.27 (d, J=1.6 Hz, 1H), 7.18 (d, J=8.4 Hz, 1H),4.12-4.40 (m, 1H), 3.42-3.36 (m, 2H), 3.19-3.12 (m, 2H), 2.96-2.89 (m,2H), 2.41 (s, 3H).

6. Synthesis of7-bromo-3-tosyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-1-amine

A mixture of7-bromo-3-tosyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-1-amine (1.2 g,3.04 mmol) in HBr/HOAc (33%, 20 mL) was stirred at 70° C. for 12 h.After cooling down, the mixture was diluted with EtOAc (60 mL) and theresulting precipitate was filtered and dried under vacuum to give7-bromo-3-tosyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-1-amine (870 mg,yield: 71%) as a white solid. ESI-MS (M+H)⁺: 241.1. ¹H NMR (400 MHz,CDCl₃) δ: 7.65-7.63 (m, 2H), 7.25 (d, J=8.8 Hz, 1H), 5.17-5.14 (m, 1H),3.84-3.80 (m, 1H), 3.69-3.65 (m, 1H), 3.44-3.40 (m, 2H), 3.27-3.14 (m,2H).

7. Synthesis of tert-butyl1-amino-7-bromo-4,5-dihydro-1H-benzo[d]azepine-3(2H)-carboxylate

To a mixture of7-bromo-3-tosyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-1-amine (680 mg,1.7 mmol) and triethylamine (515 mg, 5.1 mmol) in CH₂Cl₂ (10 mL), Boc₂O(333 mg, 1.0 mmol) was added. The mixture was stirred at rt for 2 h.After diluting with CH₂Cl₂ (100 mL), the organic layer was washed withwater (30 mL) and brine (30 mL), dried (Na₂SO₄), filtered andconcentrated in vacuo to give tert-butyl1-amino-7-bromo-4,5-dihydro-1H-benzo[d]azepine-3(2H)-carboxylate (450mg, yield: 77%) as a yellow oil. ESI-MS (M+H)⁺: 341.0. ¹H NMR (400 MHz,CDCl₃) δ: 7.31 (d, J=8.0 Hz, 1H), 7.26 (s, 1H), 7.19-7.11 (m, 1H),4.17-4.10 (m, 1H), 3.83-3.66 (m, 2H), 3.48-3.45 (m, 1H), 3.37-3.14 (m,2H), 2.78-2.73 (m, 1H), 1.47 (s, 9H).

8. Synthesis of tert-butyl7-bromo-1-(5-(tert-butyl)-1,2,4-oxadiazole-3-carboxamido)-4,5-dihydro-1H-benzo[d]azepine-3(2H)-carboxylate

To a mixture of potassium 5-(tert-butyl)-1,2,4-oxadiazole-3-carboxylate(358 mg, 1.5 mmol) in CH₂Cl₂ (10 mL), (COCl)₂ (567 mg, 4.5 mmol) and DMF(cat.) were added at 0° C. The mixture was stirred at room temperaturefor 1 h. The mixture was concentrated. The residue was dried in vacuo,then dissolved in CH₂Cl₂ (10 mL), tert-butyl1-amino-7-bromo-4,5-dihydro-1H-benzo[d]azepine-3(2H)-carboxylate (408mg, 1.5 mmol) and triethylamine (454 mg, 4.5 mmol) were added. Themixture was stirred at rt for 12 h and diluted with CH₂Cl₂ (100 mL). Theorganic phase was washed with water (50 mL) and brine (50 mL) andconcentrated. The residue was purified by silica gel column (PE(petroleum ether): EtOAc (ethyl acetate)=4:1) to give tert-butyl7-bromo-1-(5-(tert-butyl)-1,2,4-oxadiazole-3-carboxamido)-4,5-dihydro-1H-benzo[d]azepine-3(2H)-carboxylate (290 mg, yield: 38%) as a white solid. ESI-MS(M+H-56)⁺: 437.0. ¹H NMR (400 MHz, CD₃OD) δ 7.42-7.38 (m, 2H), 7.26 (d,J=7.6 Hz, 1H), 5.39 (d, J=5.2 Hz, 1H), 4.14-4.08 (m, 1H), 4.01-3.87 (m,1H), 3.75-3.70 (m, 2H), 3.56-3.46 (m, 1H), 3.24-3.15 (m, 1H), 3.00-2.91(m, 1H), 1.48 (s, 9H), 1.38 (s, 9H).

9. Synthesis of 2-chloro-4-methoxypyrimidine

To a solution of 2,4-dichloropyrimidine (7.5 g, 50 mmol,) in MeOH (80mL) was added dropwise into a solution of NaOMe (2.84 g, 52.5 mmol) inMeOH (20 mL) at 0° C. The reaction mixture was stirred at 0° C. for 2 h.The reaction mixture was concentrated in vacuo to give crude product.The crude product was poured into 150 mL of water. The aqueous phase wasextracted with EtOAc (100 mL). The organic layer was dried with Na₂SO₄and concentrated in vacuum to give 2-chloro-4-methoxypyrimidine (5.9 g,yield: 82%) as a light yellow solid. ESI-MS (M+H)⁺: 145.0. ¹H NMR (400MHz, CDCl₃) δ: 8.27 (d, J=6.0 Hz, 1H), 6.65 (d, J=6.0 Hz, 1H), 3.99 (s,3H).

10. Synthesis of 4-methoxy-N-(1-methyl-1H-pyrazol-4-yl)pyrimidin-2-amine

To a solution of 2-chloro-4-methoxypyrimidine (120 g, 0.83 mol) indioxane (2 L) was added 1-methyl-1H-pyazol-4-amine hydrochloride (111 g,0.83 mol), Cs₂CO₃ (0.83 kg, 2.5 mol), S-Phos (13.3 g, 0.03 mol) andPd₂(dba)₃ (16.7 g, 0.02 mol). The reaction mixture was stirred at 120°C. under N₂ for 4 h. The reaction mixture was cooled to room temperatureand water (4 L) was added. The layers were separated and the aqueousphase was extracted with EtOAc (3×2 L). The combined organic layers werewashed with brine (3 L), dried (Na₂SO₄) and concentrated. The crudematerial was purified by silica gel chromatography (PE:EtOAc=5:1 to 1:1)to give 4-methoxy-N-(1-methyl-1H-pyrazol-4-yl)pyrimidin-2-amine (73 g,yield: 43%) as a tan solid. ESI-MS (M+H)⁺: 205.8.

11. Synthesis of 4-chloro-N-(1-methyl-1H-pyrazol-4-yl)pyrimidin-2-amine

To 4-methoxy-N-(1-methyl-1H-pyrazol-4-yl)pyrimidin-2-amine (1.4 kg, 6.8mol) was added HBr (11.2 L, 38% aqueous). The reaction mixture washeated to 100° C. and stirred at that temperature for 2 h. The reactionmixture was concentrated and then POCl₃ (11.2 L) was added. The reactionmixture was heated to 100° C. and stirred at that temperature for 16 h.The reaction mixture was cooled to room temperature and concentrated.Water (10 L) was added to the residue and the pH of the solution wasadjusted to pH=14 with aqueous NaOH (4 M). The basic aqueous phase wasextracted with EtOAc (3×10 L). The combined organic layers were washedwith brine (9 L), dried (Na₂SO₄) and concentrated. The crude materialwas purified by silica gel chromatography (PE:EtOAc=5:1 to 2:1) to give4-chloro-N-(1-methyl-1H-pyrazol-4-yl)pyrimidin-2-amine as a white solid(770 g, yield: 54%). ESI-MS (M+H)⁺: 210.0.

12. Synthesis of tert-butyl1-(5-(tert-butyl)-1,2,4-oxadiazole-3-carboxamido)-7-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-4,5-dihydro-1H-benzo[d]azepine-3(2H)-carboxylate

To a mixture of tert-butyl7-bromo-1-(5-(tert-butyl)-1,2,4-oxadiazole-3-carboxamido)-4,5-dihydro-1H-benzo[d]azepine-3(2H)-carboxylate(510 mg, 1.03 mmol) and PinB-BPin (263 mg, 1.0 mmol) in dry 1,4-dioxane(10 mL), KOAc (303 mg, 3.09 mmol) and Pd(dppf)Cl₂.CH₂Cl₂ (81 mg, 0.1mmol) were added quickly under N₂. The mixture was stirred at 100° C.for 12 h under N₂. After cooling down,4-chloro-N-(1-methyl-1H-pyrazol-4-yl)pyrimidin-2-amine (237 mg, 1.13mmol), K₂CO₃ (213 mg, 1.54 mmol) and H₂O (2.5 mL) were added. Themixture was stirred at 100° C. for 12 h under N₂. After cooling down,the mixture was concentrated and purified by silica gel column(CH₂Cl₂:PE:EtOAc=1:1:1) to give tert-butyl1-(5-(tert-butyl)-1,2,4-oxadiazole-3-carboxamido)-7-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-4,5-dihydro-1H-benzo[d]azepine-3(2H)-carboxylate(250 mg, yield: 41%) as a yellow solid. ESI-MS (M+H)⁺: 588.2. ¹H NMR(400 MHz, CD₃OD) δ: 8.41 (d, J=4.8 Hz, 1H), 7.99-7.98 (m, 3H), 7.64 (s,1H), 7.49 (d, J=8.4 Hz, 1H), 7.21 (d, J=5.2 Hz, 1H), 5.54-5.47 (m, 1H),4.18-4.05 (m, 1H), 3.97-3.90 (m, 4H), 3.87-3.76 (m, 2H), 3.65-3.57 (m,1H), 3.15-3.11 (m, 1H), 1.49 (s, 9H), 1.39 (s, 9H).

13. Synthesis of5-(tert-butyl)-N-(7-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-1-yl)-1,2,4-oxadiazole-3-carboxamide

To a solution of TFA (1 mL) in CH₂Cl₂ (2 mL) was added tert-butyl1-(5-(tert-butyl)-1,2,4-oxadiazole-3-carboxamido)-7-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-4,5-dihydro-1H-benzo[d]azepine-3(2H)-carboxylate(230 mg, 0.39 mmol). The mixture was stirred at rt for 1 h, thenconcentrated and purified by prep-HPLC (CH₃CN/water NH₄HCO₃ 0.05% asmobile phrase) to give5-(tert-butyl)-N-(7-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-1-yl)-1,2,4-oxadiazole-3-carboxamide(120 mg, yield: 58%). ESI-MS (M+H)⁺: 488.3. ¹H NMR (400 MHz, CD₃OD) δ:8.37-8.35 (m, 1H), 7.95 (s, 1H), 7.91-7.88 (m, 2H), 7.63 (s, 1H), 7.46(d, J=7.6 Hz, 1H), 7.15 (d, J=4.8 Hz, 1H), 5.34 (d, J=7.2 Hz, 1H), 3.95(s, 3H), 3.24-3.19 (m, 1H), 3.11-3.08 (m, 3H), 2.99-2.94 (m, 2H), 1.49(s, 9H).

Example 2.(R)-5-(tert-butyl)-N-(8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(oxetan-3-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1,2,4-oxadiazole-3-carboxamide(compound 2)

Method 1 1. Preparation of 3-(3-Bromo-benzylamino)-propionic Acid EthylEster

To a solution of ethyl 3-aminopropanoate (46.0 g, 0.3 mol) and3-bromobenzaldehyde (55.5 g, 0.3 mol) in MeOH (1.2 L) were addedtriethylamine (60.7 g, 0.6 mol) and NaCNBH₃ (56.5 g, 0.9 mol)portion-wise. The resulting mixture was stirred at rt for 4 h. Thereaction mixture was concentrated in vacuo and the residue was dilutedwith water (600 mL). The mixture was extracted with EtOAc (3×500 mL).The combined organic layer was washed with brine (100 mL), dried overanhydrous Na₂SO₄, filtered and concentrated in vacuo to give3-(3-bromo-benzylamino)-propionic acid ethyl ester (46.5 g, yield: 54%)as a light yellow oil. ¹H NMR (DMSO-d₆, 300 MHz): δ 7.52 (s, 1H), 7.40(d, J=7.5 Hz, 1H), 7.31-7.25 (m, 2H), 4.04 (q, J=7.2 Hz, 2H), 3.67 (s,2H), 2.69 (t, J=7.2 Hz, 2H), 2.42 (t, J=6.9 Hz, 2H), 1.17 (t, J=6.9 Hz,3H).

2. Preparation of3-[(3-Bromo-benzyl)-(toluene-4-sulfonyl)-amino]-propionic Acid EthylEster

To a solution of 3-(3-bromo-benzylamino)-propionic acid ethyl ester(45.6 g, 0.16 mol) in pyridine (500 mL) was added TosCl (61.0 g, 0.32mol) at rt. The reaction mixture was stirred at 120° C. for 16 h. Thesolvent was removed in vacuo to give the crude product. The crudeproduct was purified by column chromatography on silica gel (petroleumether:EtOAc=10:1 to 5:1) to afford3-[(3-Bromo-benzyl)-(toluene-4-sulfonyl)-amino]-propionic acid ethylester (61 g, yield: 88%) as a light yellow oil. ¹H NMR (DMSO-d₆, 300MHz): δ 7.74 (d, J=8.4 Hz, 2H), 7.49-7.41 (m, 4H), 7.31 (d, J=5.1 Hz,2H), 4.33 (s, 2H), 3.93 (q, J=7.2 Hz, 2H), 3.32 (t, J=7.2 Hz, 2H), 2.41(s, 3H), 2.36 (t, J=6.9 Hz, 2H), 1.10 (t, J=6.9 Hz, 3H).

3. Preparation of3-[(3-Bromo-benzyl)-(toluene-4-sulfonyl)-amino]-propionic Acid

To a solution of3-[(3-Bromo-benzyl)-(toluene-4-sulfonyl)-amino]-propionic acid ethylester (60.0 g, 0.14 mol) in a mixed solvent of EtOH (600 mL) and H₂O (60mL) was added NaOH (11.2 g, 0.28 mol) portion-wise, the reactionsolution was stirred at 60° C. for 4 h. The reaction solution was cooledto 0° C. and acidified to pH=5 with concentrated HCl. The solvent wasconcentrated in vacuo to give a residue which was extracted with EtOAc(3×150 mL). The organic layer was dried with Na₂SO₄, filtered, andconcentrated in vacuo to give3-[(3-Bromo-benzyl)-(toluene-4-sulfonyl)-amino]-propionic acid (45.2 g,yield: 78.6%) as a white solid. ¹H NMR (DMSO-d₆, 300 MHz): δ 12.28 (br,1H), 7.74 (d, J=8.1 Hz, 2H), 7.49-7.41 (m, 4H), 7.32 (d, J=5.1 Hz, 2H),4.33 (s, 2H), 3.29 (t, J=6.9 Hz, 2H), 2.41 (s, 3H), 2.27 (t, J=7.5 Hz,2H).

4. Preparation of3-[(3-Bromo-benzyl)-(toluene-4-sulfonyl)-amino]-propionyl Chloride

To a solution of3-[(3-Bromo-benzyl)-(toluene-4-sulfonyl)-amino]-propionic acid (45.2 g,0.11 mol) in CH₂Cl₂ (1000 mL) were added dropwise DMF (1 mL) and oxalylchloride (27.9 g, 0.22 mol) portion-wise. The reaction solution wasstirred at 55° C. for 2 h. The mixture was concentrated in vacuo to givethe crude 3-[(3-Bromo-benzyl)-(toluene-4-sulfonyl)-amino]-propionylchloride (47.2 g, yield: 99%) as a black oil which was used in the nextstep without further purification.

5. Preparation of8-Bromo-2-(toluene-4-sulfonyl)-1,2,3,4-tetrahydro-benzo[c]azepin-5-one

To a solution of3-[(3-Bromo-benzyl)-(toluene-4-sulfonyl)-amino]-propionyl chloride (47.0g, 0.11 mol) in anhydrous CH₂Cl₂ (1200 mL) was added AlCl₃ (29.3 g, 0.22mol) portion-wise at rt. The reaction mixture was stirred at 55° C. for2 h. The reaction mixture was poured into ice water (1.2 L) andextracted with (500 mL). The organic layer was concentrated in vacuo togive the crude product. The crude product was purified by columnchromatography on silica gel (petroleum ether:EtOAc=5:1 to 2:1) toafford8-bromo-2-(toluene-4-sulfonyl)-1,2,3,4-tetrahydro-benzo[c]azepin-5-one(35 g, yield: 81%) as a white solid. ¹H NMR (DMSO-d₆, 300 MHz): δ 7.65(d, J=8.4 Hz, 3H), 7.60-7.51 (m, 2H), 7.36 (d, J=8.1 Hz, 2H), 4.68 (s,2H), 3.42 (t, J=9.2 Hz, 2H), 2.96 (t, J=6.3 Hz, 2H), 2.37 (s, 3H).

6. Preparation of[8-Bromo-2-(toluene-4-sulfonyl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl]-carbamicAcid Tert-Butyl Ester

To a solution of8-bromo-2-(toluene-4-sulfonyl)-1,2,3,4-tetrahydro-benzo[c]azepin-5-one(32.0 g, 0.08 mol) in EtOH (600 mL) were added NH₄OAc (18.5 g, 0.24 mol)and NaCNBH₃ (14.9 g, 0.24 mol) portion-wise at rt. Then the reactionmixture was stirred at 95° C. for 16 h. The mixture was poured into icewater (500 mL) and then EtOH was removed in vacuo. The residue wasextracted with CH₂Cl₂ (3×500 mL). The combined solvent was concentrated.The residue was redissolved in CH₂Cl₂ (300 mL) and were addedtriethylamine (12.2 g, 0.12 mol) and (Boc)₂O (34.6 g, 0.12 mol) at rt.The mixture was stirred at rt for 4 h and then concentrated in vacuo togive the crude product. The crude product was purified by columnchromatography on silica gel (peteroleum ether:EtOAc=8:1 to 2:1) toafford[8-bromo-2-(toluene-4-sulfonyl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl]-carbamicacid tert-butyl ester (16.7 g, yield: 42%) as a white solid. ¹H NMR(DMSO d₆, 300 MHz): δ 7.62-7.51 (m, 2H), 7.47 (d, J=9.9 Hz, 1H),7.41-7.34 (m, 3H), 7.10 (d, J=8.4 Hz, 1H), 4.81-4.74 (m, 1H), 4.53 (d,J=15.0 Hz, 1H), 4.28 (d, J=15.3 Hz, 1H), 3.64-3.57 (m, 1H), 3.41-3.30(m, 1H), 2.35 (s, 3H), 1.85-1.77 (m, 1H), 1.69-1.63 (m, 1H), 1.36 (s,9H).

7. Preparation of8-Bromo-2-(toluene-4-sulfonyl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-ylamine

A solution of[8-bromo-2-(toluene-4-sulfonyl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl]-carbamicacid tert-butyl ester (14.8 g, 0.03 mol) in HCl/EtOAc (150 mL) wasstirred at 25° C. for 4 h. The resulting solid was filtered and washedwith MeOH and Et₂O to give the product8-bromo-2-(toluene-4-sulfonyl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-ylamine(10.5 g, yield: 89%) as a white solid. ¹H NMR (DMSO-d₆, 300 MHz): δ 8.79(br, 3H), 7.64-7.58 (m, 3H), 7.53 (s, 1H), 7.36 (d, J=8.4 Hz, 2H), 7.15(d, J=8.4 Hz, 1H), 4.71-4.61 (m, 2H), 4.31 (d, J=15.3 Hz, 1H), 3.82 (d,J=18.3 Hz, 1H), 2.38 (s, 3H), 2.14-2.07 (m, 1H), 1.77-1.71 (m, 1H).LC-MS: m/z 395.0/397.0 [M+H]⁺.

8. Synthesis of 8-bromo-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-amine

A solution of8-bromo-2-(toluene-4-sulfonyl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-ylamine(2.00 g, 5.06 mmol) in HBr (33% solution in acetic acid, 20 mL) washeated at 50° C. for 12 h. After cooling to rt, the mixture was dilutedEtOAc (50 mL). The white solid was collected by filtration and dried invacuo to afford crude product8-bromo-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-amine (1.66 g, yield:82%), which was used directly in the next step. ESI-MS (M+H)⁺241.1. ¹HNMR (400 MHz, CD₃OD) δ: 7.72-7.55 (m, 2H), 7.18 (d, J=8.4 Hz, 1H),4.99-4.98 (m, 1H), 4.51 (d, J=14.4 Hz, 1H), 4.39 (d, J=14.4 Hz, 1H),3.62-3.49 (m, 2H), 2.38-2.24 (m, 1H), 2.16-2.00 (m, 1H).

9. Synthesis of tert-butyl5-amino-8-bromo-4,5-dihydro-1H-benzo[c]azepine-2(3H)-carboxylate

To a solution of 8-bromo-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-amine(640 mg, 1.60 mmol) and triethylamine (490 mg, 4.8 mmol) in CH₂Cl₂ (20mL) was added (Boc)₂O (314 mg, 1.44 mmol). The mixture was stirred at rtfor 1 h. After diluting with CH₂Cl₂ (100 mL), the mixture was washedwith brine (20 mL×2). The organic phase was concentrated in vacuo andthe residue was purified by prep-HPLC (CH₃CN/H₂O with 0.05% NH₃.H₂O asmobile phase) to give tert-butyl5-amino-8-bromo-4,5-dihydro-1H-benzo[c]azepine-2(3H)-carboxylate as acolorless oil (364 mg, yield: 67%). ESI-MS (M+H)⁺: 341.1.

10. The Preparation of tert-butyl8-bromo-5-(5-(tert-butyl)-1,2,4-oxadiazole-3-carboxamido)-4,5-dihydro-1H-benzo[c]azepine-2(3H)-carboxylate

Synthesis of tert-butyl8-bromo-5-(5-(tert-butyl)-1,2,4-oxadiazole-3-carboxamido)-4,5-dihydro-1H-benzo[c]azepine-2(3H)-carboxylatewas similar to that of tert-butyl7-bromo-1-(5-(tert-butyl)-1,2,4-oxadiazole-3-carboxamido)-4,5-dihydro-1H-benzo[d]azepine-3(2H)-carboxylate in Example 1, Step 8. The crude product was purified byprep-HPLC (CH₃CN/H₂O with 0.05% NH₄HCO₃ as mobile phase) to givetert-butyl8-bromo-5-(5-(tert-butyl)-1,2,4-oxadiazole-3-carboxamido)-4,5-dihydro-1H-benzo[c]azepine-2(3H)-carboxylateas a yellow solid (4.5 g, yield: 70%). ESI-MS (M+H)⁺: 493.3.

11. The Preparation of tert-butyl5-(5-(tert-butyl)-1,2,4-oxadiazole-3-carboxamido)-8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-4,5-dihydro-1H-benzo[c]azepine-2(3H)-carboxylate

Synthesis of tert-butyl5-(5-(tert-butyl)-1,2,4-oxadiazole-3-carboxamido)-8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-4,5-dihydro-1H-benzo[c]azepine-2(3H)-carboxylatewas similar to that of tert-butyl1-(5-(tert-butyl)-1,2,4-oxadiazole-3-carboxamido)-7-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-4,5-dihydro-1H-benzo[d]azepine-3(2H)-carboxylatein Example 1, Step 12. The crude product was purified by silica gelcolumn chromatograph (EtOAc/MeOH=15:1) to give tert-butyl5-(5-(tert-butyl)-1,2,4-oxadiazole-3-carboxamido)-8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-4,5-dihydro-1H-benzo[c]azepine-2(3H)-carboxylateas yellow solid (1.2 g, yield: 28%). ESI-MS (M+H)⁺: 588.3. ¹H NMR (400MHz, CD₃OD) δ: 8.43-8.38 (m, 1H), 8.11-7.95 (m, 3H), 7.67-7.48 (m, 2H),7.25-7.24 (m, 1H), 5.67-5.63 (m, 1H), 4.84-4.77 (m, 1H), 4.55-4.50 (m,1H), 4.17-4.09 (m, 1H), 3.94-3.88 (m, 3H), 3.64-3.54 (m, 1H), 2.11-2.08(m, 2H), 1.43-1.34 (m, 9H), 1.22 (s, 9H).

12. The Preparation of5-(tert-butyl)-N-(8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1,2,4-oxadiazole-3-carboxamide

To a solution of tert-butyl5-(5-(tert-butyl)-1,2,4-oxadiazole-3-carboxamido)-8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-4,5-dihydro-1H-benzo[c]azepine-2(3H)-carboxylate(600 mg, 1.0 mmol) in CH₂Cl₂ (5 mL) was added TFA (5 mL), the mixturewas stirred 1 h at rt. After concentration, the crude product (440 mg,yield: 85%) was used in the next step without further purification.ESI-MS (M+H)⁺: 488.3.

13. The Preparation of5-(tert-butyl)-N-(8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(oxetan-3-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1,2,4-oxadiazole-3-carboxamide

To a solution of5-(tert-butyl)-N-(8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1,2,4-oxadiazole-3-carboxamide(180 mg, 0.36 mmol) and dihydrofuran-3(2H)-one (132 mg, 1.8 mmol) inMeOH (20 mL) were added NaBH₃CN (66 mg, 1.08 mmol) and ZnCl₂(246 mg, 1.8mmol). The mixture was stirred at rt for 16 h. After concentration anddiluting with water (30 mL), the mixture was extracted with EtOAc (80mL×2). The combined organic layer was washed with H₂O (60 mL) andconcentrated. The crude product was purified by prep-HPLC (CH₃CN/H₂Owith 0.05% NH₄HCO₃ as mobile phase) to give5-(tert-butyl)-N-(8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(oxetan-3-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1,2,4-oxadiazole-3-carboxamideas a yellow solid (114 mg, yield: 49%). ESI-MS (M+H)⁺: 544.3. ¹H NMR(400 MHz, CD₃OD) δ: 8.30 (d, J=5.2 Hz, 1H), 7.92-7.85 (m, 3H), 7.51 (s,1H), 7.35 (d, J=8.4 Hz, 1H), 7.11 (d, J=5.2 Hz, 1H), 5.50 (d, J=9.6 Hz,1H), 4.67-4.55 (m, 4H), 3.84-3.70 (m, 3H), 3.80 (s, 3H), 2.95-2.89 (m,1H), 2.76-2.72 (m, 1H), 2.15-2.12 (m, 1H), 1.95-1.92 (m, 1H), 1.40 (s,9H).

14. The Preparation of(R)-5-(tert-butyl)-N-(8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(oxetan-3-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1,2,4-oxadiazole-3-carboxamide

5-(tert-butyl)-N-(8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(oxetan-3-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1,2,4-oxadiazole-3-carboxamidewas subjected to SFC separation (OD-H (2×25 cm), 30% methanol/CO₂, 100bar, 60 mL/min, 220 nm, inj vol.: 1.5 mL, 9 mg/mL, methanol) and yielded34.8 mg of peak-1 (chemical purity 99%, ee>99%) and 37.1 mg of peak-2(chemical purity 99%, ee>99%).

Peak 2 was assigned as 5-tert-butyl-1,2,4-oxadiazole-3-carboxylic acid{(R)-8-[2-(1-methyl-1H-pyrazol-4-ylamino)-pyrimidin-4-yl]-2-oxetan-3-yl-2,3,4,5-tetrahydro-1H-2-benzazepin-5-yl}-amide:LCMS: Rt 0.88 min, m/z 544.00. 1H NMR (400 MHz, METHANOL-d4) δ 8.40 (d,J=5.02 Hz, 1H), 7.87-8.09 (m, 3H), 7.63 (s, 1H), 7.45 (d, J=8.28 Hz,1H), 7.20 (d, J=5.27 Hz, 1H), 5.60 (s, 1H), 4.55-4.77 (m, 4H), 3.89 (s,3H), 3.75-3.85 (m, 3H), 2.75-3.10 (m, 2H), 1.89-2.42 (m, 2H), 1.51 (s,9H).

Method 2 1. Chiral resolution of tert-butyl5-amino-8-bromo-4,5-dihydro-1H-benzo[c]azepine-2(3H)-carboxylate to givetert-butyl(R)-5-amino-8-bromo-1,3,4,5-tetrahydro-2H-benzo[c]azepine-2-carboxylatecompound with(11bS)-4-hydroxydinaphtho[2,1-d:1′,2′-f][1,3,2]dioxaphosphepine 4-oxide(1:1)

To tert-butyl5-amino-8-bromo-4,5-dihydro-1H-benzo[c]azepine-2(3H)-carboxylate (800 g,2.34 mol) was added MeOH (4.8 L) and (S)-(−)-1,1′-binaphthyl-2,2′-diylhydrogenphosphate (816.6 g, 2.34 mol). The mixture was stirred at 25° C.for 30 min and formed a yellow slurry. The slurry was stirred at reflux(70° C.) to give a yellow solution. The mixture was concentrated todryness and IPAc (3.44 L) was added. The mixture was heated to 70° C.and was stirred at that temperature for 3 h. The reaction mixture wascooled to room temperature and an additional portion of IPAc (3.44 L)was added. The reaction mixture continued to stir at room temperaturefor 16 h. The slurry was filtered on centrifuge and the cake was washedthree times, each with 7 vol IPAc. The wet cake was briefly dried togive tert-butyl(R)-5-amino-8-bromo-1,3,4,5-tetrahydro-2H-benzo[c]azepine-2-carboxylatecompound with(11bS)-4-hydroxydinaphtho[2,1-d:1′,2′-f][1,3,2]dioxaphosphepine 4-oxide(1:1) (515 g. yield: 64% ([assuming maximum recovery of 50%], 91.3% ee)as a white solid.

The recrystallization process can be repeated to increase the ee to97.2%.

2. The Preparation of tert-butyl(R)-8-bromo-5-(5-(tert-butyl)-1,2,4-oxadiazole-3-carboxamido)-1,3,4,5-tetrahydro-2H-benzo[c]azepine-2-carboxylate

To a solution of potassium 5-(tert-butyl)-1,2,4-oxadiazole-3-carboxylate(800 mg, 4.0 mmol) and oxalyl chloride (2.0 g, 16 mmol) in CH₂Cl₂ (10mL) was added DMF (cat.). The mixture was stirred at room temperaturefor 2 h, and then was concentrated with CH₂Cl₂ twice. The residue wasdiluted with CH₂Cl₂ (20 mL) and tert-butyl(R)-5-amino-8-bromo-1,3,4,5-tetrahydro-2H-benzo[c]azepine-2-carboxylatecompound with (11bR)-4-hydroxydinaphtho[2,1-d:1′,2′-f][1,3,2]dioxaphosphepine 4-oxide (1:1) (2.0 g, 3.0 mmol) andtriethylamine (900 mg, 9.0 mmol) were added. The mixture was stirred atroom temperature for 2 h and concentrated. The crude product waspurified by silica gel chromatograph y (PE:EtOAc=2:1) to give tert-butyl(R)-8-bromo-5-(5-(tert-butyl)-1,2,4-oxadiazole-3-carboxamido)-1,3,4,5-tetrahydro-2H-benzo[c]azepine-2-carboxylateas a yellow solid (1.2 g, yield: 80%). ESI-MS (M+Na)⁺: 515.1. ¹H NMR(400 MHz, CDCl₃) δ: 7.48-7.36 (m, 2H), 7.24-7.18 (m, 1H), 5.61-5.50 (m,1H), 4.70-4.51 (m, 1H), 4.38-4.29 (m, 1H), 4.05-3.85 (m, 1H), 3.53-3.48(m, 1H), 2.24-2.16 (m, 2H), 1.48 (s, 9H), 1.40-1.37 (m, 9H).

3. Synthesis of tert-butyl(R)-5-(5-(tert-butyl)-1,2,4-oxadiazole-3-carboxamido)-8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-1,3,4,5-tetrahydro-2H-benzo[c]azepine-2-carboxylate

Synthesis of tert-butyl(R)-5-(5-(tert-butyl)-1,2,4-oxadiazole-3-carboxamido)-8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-1,3,4,5-tetrahydro-2H-benzo[c]azepine-2-carboxylatewas similar to that of tert-butyl1-(5-(tert-butyl)-1,2,4-oxadiazole-3-carboxamido)-7-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-4,5-dihydro-1H-benzo[d]azepine-3(2H)-carboxylatein Example 1, Step 12. The crude material was purified by silica gelchromatography (EtOAc:MeOH=15:1) to give tert-butyl(R)-5-(5-(tert-butyl)-1,2,4-oxadiazole-3-carboxamido)-8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-1,3,4,5-tetrahydro-2H-benzo[c]azepine-2-carboxylateas a yellow solid (1.5 g, yield: 43%). ESI-MS (M+H)⁺: 588.3.

4. Synthesis of(R)-5-(tert-butyl)-N-(8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1,2,4-oxadiazole-3-carboxamide

To a solution of tert-butyl(R)-5-(5-(tert-butyl)-1,2,4-oxadiazole-3-carboxamido)-8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-1,3,4,5-tetrahydro-2H-benzo[c]azepine-2-carboxylate(1.4 g, 2.3 mmol) in CH₂Cl₂ (10 mL) was added TFA (10 mL). The mixturewas stirred for 1 h at room temperature. The reaction mixture wasconcentrated and the crude product (1.0 g, yield: 81%) was used in thenext step without further purification. ESI-MS (M+H)⁺: 488.3.

5. Synthesis of(R)-5-(tert-butyl)-N-(8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(oxetan-3-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1,2,4-oxadiazole-3-carboxamide(I-RP33)

Synthesis of(R)-5-(tert-butyl)-N-(8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(oxetan-3-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1,2,4-oxadiazole-3-carboxamidewas similar to that of5-(tert-butyl)-N-(8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(oxetan-3-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1,2,4-oxadiazole-3-carboxamidedescribed above in method 1, step 13. The crude material was purified bysilica gel chromatography (EtOAc:MeOH=20:1) to give(R)-5-(tert-butyl)-N-(8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(oxetan-3-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1,2,4-oxadiazole-3-carboxamideas a yellow solid (746 mg, Y: 67%). ESI-MS (M+H)⁺: 544.3. ¹H NMR (400MHz, CD₃OD) δ: 8.42 (d, J=5.2 Hz, 1H), 8.03-7.96 (m, 3H), 7.63 (s, 1H),7.48 (d, J=8.0 Hz, 1H), 7.23 (d, J=5.2 Hz, 1H), 5.61 (d, J=9.6 Hz, 1H),4.78-4.67 (m, 4H), 3.96-3.82 (m, 3H), 3.90 (s, 3H), 3.06-3.02 (m, 1H),2.89-2.80 (m, 1H), 2.29-2.22 (m, 1H), 2.07-2.03 (m, 1H), 1.52 (s, 9H).

Example 3.5-(tert-butyl)-N-(2-(2-hydroxyethyl)-8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1,2,4-oxadiazole-3-carboxamide(compound 3)

To a solution of5-(tert-butyl)-N-(8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1,2,4-oxadiazole-3-carboxamide(200 mg, 0.41 mmol) in CH₃CN (20 mL) were added 2-iodoethanol (141 mg,0.82 mmol) and K₂CO₃ (170 mg, 1.23 mmol). The mixture was stirred at 80°C. for 2 h. The mixture was diluted with EtOAc (100 mL), washed withwater (60 mL) and concentrated. The crude product was purified byprep-HPLC (CH₃CN/H₂O with 0.05% NH₄HCO₃ as mobile phase) to give5-(tert-butyl)-N-(2-(2-hydroxyethyl)-8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1,2,4-oxadiazole-3-carboxamideas a yellow solid (90 mg, yield: 32%). ESI-MS (M+H)⁺: 532.3. ¹H NMR (400MHz, CD₃OD) δ: 8.43 (d, J=5.2 Hz, 1H), 8.04-8.00 (m, 3H), 7.64 (s, 1H),7.47 (d, J=8.0 Hz, 1H), 7.25 (d, J=5.0 Hz, 1H), 5.60 (d, J=9.6 Hz, 1H),4.22-4.10 (m, 2H), 3.91 (s, 3H), 3.75 (t, J=6.0 Hz, 2H), 3.28-3.21 (m,2H), 2.69-2.65 (m, 2H), 2.31-2.27 (m, 1H), 2.00-1.97 (m, 1H), 1.53 (s,9H).

Example 4.5-(tert-butyl)-N-(8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(methylsulfonyl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1,2,4-oxadiazole-3-carboxamide(compound 4)

Synthesis of5-(tert-butyl)-N-(8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(methylsulfonyl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1,2,4-oxadiazole-3-carboxamidewas similar to that of5-(tert-butyl)-N-(8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(methylsulfonyl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1,3,4-oxadiazole-2-carboxamidein Example 15. The crude product was purified by prep-HPLC (CH₃CN/H₂Owith 0.05% NH₄HCO₃ as mobile phase) to give5-(tert-butyl)-N-(8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(methylsulfonyl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1,2,4-oxadiazole-3-carboxamideas a yellow solid (98 mg, yield: 60%). ESI-MS (M+H)⁺: 566.2. ¹H NMR (400MHz, CDCl₃) δ: 8.45 (d, J=4.8 Hz, 1H), 8.02 (s, 1H), 7.94-7.92 (m, 2H),7.57-7.48 (m, 3H), 7.07 (d, J=5.2 Hz, 1H), 6.96 (s, 1H), 5.72 (t, J=8.8Hz, 1H), 4.85-4.81 (m, 1H), 4.57-4.53 (m, 1H), 4.03-3.97 (m, 1H), 3.93(s, 3H), 3.66-3.63 (m, 1H), 2.74 (s, 3H), 2.39-2.21 (m, 2H), 1.49 (s,9H).

Example 5.5-(tert-butyl)-N-(8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(oxetan-3-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1,2,4-oxadiazole-3-carboxamide(compound 5)

To a solution of5-(tert-butyl)-N-(8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1,2,4-oxadiazole-3-carboxamide(180 mg, 0.36 mmol) and dihydrofuran-3(2H)-one (132 mg, 1.8 mmol) inMeOH (20 mL) were added NaBH₃CN (66 mg, 1.08 mmol) and ZnCl₂(246 mg, 1.8mmol). The mixture was stirred at rt for 16 h. After concentration anddiluting with water (30 mL), the mixture was extracted with EtOAc (80mL×2). The combined organic layer was washed with H₂O (60 mL) andconcentrated. The crude product was purified by prep-HPLC (CH₃CN/H₂Owith 0.05% NH₄HCO₃ as mobile phase) to give5-(tert-butyl)-N-(8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(oxetan-3-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1,2,4-oxadiazole-3-carboxamideas a yellow solid (114 mg, yield: 49%). ESI-MS (M+H)⁺: 544.3. ¹H NMR(400 MHz, CD₃OD) δ: 8.30 (d, J=5.2 Hz, 1H), 7.92-7.85 (m, 3H), 7.51 (s,1H), 7.35 (d, J=8.4 Hz, 1H), 7.11 (d, J=5.2 Hz, 1H), 5.50 (d, J=9.6 Hz,1H), 4.67-4.55 (m, 4H), 3.84-3.70 (m, 3H), 3.80 (s, 3H), 2.95-2.89 (m,1H), 2.76-2.72 (m, 1H), 2.15-2.12 (m, 1H), 1.95-1.92 (m, 1H), 1.40 (s,9H).

Example 6.5-(tert-butyl)-N-(2-(3-hydroxycyclobutyl)-8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1,2,4-oxadiazole-3-carboxamide(compound 6)

Synthesis of5-(tert-butyl)-N-(2-(3-hydroxycyclobutyl)-8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1,2,4-oxadiazole-3-carboxamidewas similar to that of5-(tert-butyl)-N-(8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(oxetan-3-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1,2,4-oxadiazole-3-carboxamidein Example 5. The crude product was purified by silica gelchromatography (EtOAc:MeOH=10:1) to give5-(tert-butyl)-N-(2-(3-hydroxycyclobutyl)-8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1,2,4-oxadiazole-3-carboxamideas a yellow solid (102 mg, yield: 53%). ESI-MS (M+H)⁺: 557.7. ¹H NMR(400 MHz, CD₃OD) δ: 8.29 (d, J=5.2 Hz, 1H), 7.87 (s, 3H), 7.50 (s, 1H),7.32 (d, J=8.8 Hz, 1H), 7.09 (d, J=5.6 Hz, 1H), 5.45 (d, J=10.0 Hz, 1H),3.86-3.78 (m, 3H), 3.75 (s, 3H), 3.09-3.06 (m, 1H), 2.80-2.74 (m, 1H),2.50-2.39 (m, 3H), 2.14-2.05 (m, 1H), 1.88-1.85 (m, 1H), 1.72-1.69 (m,2H), 1.41 (s, 9H).

Example 7.5-(tert-butyl)-N-(8-(2-((1-ethyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(oxetan-3-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1,2,4-oxadiazole-3-carboxamide(compound 7)

1. Synthesis of 4-methoxy-N-(1-ethyl-1H-pyrazol-4-yl)pyrimidin-2-amine

Synthesis of 4-methoxy-N-(1-methyl-1H-pyrazol-4-yl)pyrimidin-2-amine wassimilar to that of4-methoxy-N-(1-methyl-1H-pyrazol-4-yl)pyrimidin-2-amine in Example 1,Step 10. The crude material was purified by silica gel chromatography(PE:EtOAc=1:1) to give4-methoxy-N-(1-ethyl-1H-pyrazol-4-yl)pyrimidin-2-amine (420 mg, yield:43%) as a tan solid. ESI-MS (M+H)⁺: 220.1.

2. Synthesis of 4-chloro-N-(1-eethyl-1H-pyrazol-4-yl)pyrimidin-2-amine

To 4-methoxy-N-(1-ethyl-1H-pyrazol-4-yl)pyrimidin-2-amine (420 mg, 1.9mmol) was added HBr (5 mL, 48% aqueous). The reaction mixture was heatedto 100° C. and stirred at that temperature for 2 h. The reaction mixturewas concentrated and then POCl₃ (5 mL) was added. The reaction mixturewas heated to 100° C. and stirred at that temperature for 16 h. Thereaction mixture was cooled to room temperature and poured intoice-water. The pH of the solution was adjusted to pH=8 with aqueous NaOH(5 M). The basic aqueous phase was extracted with EtOAc (2×30 mL). Thecombined organic layers were washed with brine (100 mL), dried (Na₂SO₄)and concentrated. The crude material was purified by silica gelchromatography (PE:EtOAc=1:1) to give4-chloro-N-(1-ethyl-1H-pyrazol-4-yl)pyrimidin-2-amine as a white solid(220 mg, yield: 51%). ESI-MS (M+H)⁺: 224.1.

3. Synthesis of tert-butyl5-(5-(tert-butyl)-1,2,4-oxadiazole-3-carboxamido)-8-(2-((1-ethyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-1,3,4,5-tetrahydro-2H-benzo[c]azepine-2-carboxylate

To a mixture of tert-butyl8-bromo-5-(5-(tert-butyl)-1,2,4-oxadiazole-3-carboxamido)-1,3,4,5-tetrahydro-2H-benzo[c]azepine-2-carboxylate(560 mg, 1.13 mmol) and PinB-BPin (288 mg, 1.10 mmol) in dry 1,4-dioxane(11 mL), KOAc (332 mg, 3.39 mmol) and Pd(dppf)Cl₂.CH₂Cl₂ (89 mg, 0.11mmol) were added quickly under N₂. The mixture was stirred at 100° C.for 12 h under N₂. After cooling down,4-chloro-N-(1-ethyl-1H-pyrazol-4-yl)pyrimidin-2-amine (301 mg, 1.35mmol), K₂CO₃ (312 mg, 2.26 mmol), Pd(dppf)Cl₂.CH₂Cl₂ (89 mg, 0.11 mmol)and H₂O (2.5 mL) were added. The mixture was stirred at 80° C. for 2 hunder N₂. After cooling down, the mixture was concentrated and purifiedby silica gel column (PE:EtOAc=3:1) to give tert-butyl5-(5-(tert-butyl)-1,2,4-oxadiazole-3-carboxamido)-8-(2-((1-ethyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-1,3,4,5-tetrahydro-2H-benzo[c]azepine-2-carboxylate(200 mg, yield: 29%) as a yellow solid. ESI-MS (M+H)⁺: 602.2.

4. The Preparation of5-(tert-butyl)-N-(8-(2-((1-ethyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1,2,4-oxadiazole-3-carboxamide

To a solution of tert-butyl5-(5-(tert-butyl)-1,2,4-oxadiazole-3-carboxamido)-8-(2-((1-ethyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-1,3,4,5-tetrahydro-2H-benzo[c]azepine-2-carboxylate(200 mg, 0.33 mmol) in CH₂Cl₂ (5 mL) was added TFA (5 mL), the mixturewas stirred 1 h at rt. After concentration, the crude product (166 mg,yield: 100%) was used in the next step without further purification.ESI-MS (M+H)⁺: 502.7.

5. Synthesis of5-(tert-butyl)-N-(8-(2-((1-ethyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(oxetan-3-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1,2,4-oxadiazole-3-carboxamide(I-RP1)

To a solution of5-(tert-butyl)-N-(8-(2-((1-ethyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1,2,4-oxadiazole-3-carboxamide(166 mg, 0.33 mmol) and dihydrofuran-3(2H)-one (119 mg, 1.65 mmol) inMeOH (18 mL) were added NaBH₃CN (21 mg, 0.33 mmol) and ZnCl₂ (90 mg,0.66 mmol). The mixture was stirred at rt for 3 h. After concentrationand diluting with water (30 mL), the mixture was extracted with EtOAc(80 mL×2).

The combined organic layer was washed with H₂O (60 mL) and concentrated.The crude product was purified by prep-TLC (CH₂Cl₂:MeOH=20:1) to give5-(tert-butyl)-N-(8-(2-((1-ethyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(oxetan-3-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1,2,4-oxadiazole-3-carboxamideas a yellow solid (60 mg, yield: 32%). ESI-MS (M+H)⁺: 557.7. ¹H NMR (400MHz, CDCl₃) δ: 8.42 (d, J=5.2 Hz, 2H), 7.90 (s, 1H), 7.85 (d, J=8.0 Hz,1H), 7.79 (s, 1H), 7.57-7.53 (m, 2H), 7.04 (d, J=5.2 Hz, 1H), 5.71 (t,J=8.4 Hz, 1H), 4.82-4.66 (m, 4H), 4.17 (q, J=7.2 Hz, 2H), 3.91-3.72 (m,3H), 2.99-2.92 (m, 1H), 2.63-2.58 (m, 1H), 2.40-2.34 (m, 1H), 2.15-2.07(m, 1H), 1.51 (t, J=7.6 Hz, 3H), 1.45 (s, 9H).

Example 8.5-(tert-butyl)-N-(8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(tetrahydro-2H-pyran-4-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1,2,4-oxadiazole-3-carboxamide(compound 8)

Synthesis of5-(tert-butyl)-N-(8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(tetrahydro-2H-pyran-4-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1,2,4-oxadiazole-3-carboxamidewas similar to that of5-(tert-butyl)-N-(8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(tetrahydro-2H-pyran-4-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1,3,4-oxadiazole-2-carboxamidein Example 12, Step 4. The crude product was purified by prep-HPLC(CH₃CN/H₂O with 0.05% NH₄HCO₃ as mobile phase) to give5-(tert-butyl)-N-(8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(tetrahydro-2H-pyran-4-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1,2,4-oxadiazole-3-carboxamideas a yellow solid (20 mg, yield: 14%). ESI-MS (M+H)⁺: 572.3. ¹H NMR (400MHz, CD₃OD) δ: 8.30 (s, 1H), 7.91-7.86 (m, 3H), 7.53 (s, 1H), 7.36 (d,J=8.0 Hz, 1H), 7.10 (d, J=5.6 Hz, 1H), 5.48 (d, J=9.2 Hz, 1H), 4.19-3.88(m, 4H), 3.78 (s, 3H), 3.30-3.21 (m, 2H), 3.16-3.03 (m, 2H), 2.67-2.62(m, 1H), 2.16-2.11 (m, 1H), 1.96-1.83 (m, 3H), 1.64-1.52 (m, 2H), 1.38(s, 9H).

Example 9.(R)-5-(tert-butyl)-N-(8-(2-((1,5-dimethyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(2-hydroxyethyl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1,2,4-oxadiazole-3-carboxamide(compound 9)

1. Synthesis of tert-butyl(R)-5-(5-(tert-butyl)-1,2,4-oxadiazole-3-carboxamido)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,4,5-tetrahydro-2H-benzo[c]azepine-2-carboxylate

A mixture of tert-butyl(R)-8-bromo-5-(5-(tert-butyl)-1,2,4-oxadiazole-3-carboxamido)-1,3,4,5-tetrahydro-2H-benzo[c]azepine-2-carboxylate(1.2 g, 2.43 mmol),4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (650 mg,2.56 mmol), KOAc (477 mg, 4.86 mmol) and Pd(dppf)Cl₂.DCM (196 mg, 0.24mmol) in 30 mL 1,4-dioxane was stirred at 90° C. for 2 h under nitrogen.After cooling to room temperature, the mixture was diluted with EtOAc(200 mL), washed with water (50 mL×2), dried with Na₂SO₄ andconcentrated to give tert-butyl(R)-5-(5-(tert-butyl)-1,2,4-oxadiazole-3-carboxamido)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,4,5-tetrahydro-2H-benzo[c]azepine-2-carboxylatewhich was used for the next step without further purification. ESI-MS(M+H)⁺: 541.3.

2. Synthesis of tert-butyl(R)-5-(5-(tert-butyl)-1,2,4-oxadiazole-3-carboxamido)-8-(2-chloropyrimidin-4-yl)-1,3,4,5-tetrahydro-2H-benzo[c]azepine-2-carboxylate

A mixture of tert-butyl(R)-5-(5-(tert-butyl)-1,2,4-oxadiazole-3-carboxamido)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,4,5-tetrahydro-2H-benzo[c]azepine-2-carboxylate(1.31 g, 2.43 mmol), 2,4-dichloropyrimidine (344 mg, 2.31 mmol),Pd(dppf)Cl₂ (196 mg, 0.24 mmol) and K₂CO₃ (672 mg, 4.86 mmol) in 20 mLof dioxane/H₂O (4:1) was stirred at 90° C. for 12 h under N₂ atmosphere.After removing the solvent, the residue was purified by silica-gelchromatography (CH₂Cl₂:MeOH=20:1) to give tert-butyl(R)-5-(5-(tert-butyl)-1,2,4-oxadiazole-3-carboxamido)-8-(2-chloropyrimidin-4-yl)-1,3,4,5-tetrahydro-2H-benzo[c]azepine-2-carboxylateas a yellow solid (900 mg, yield: 70% for two steps). ESI-MS (M+H)⁺:527.2.

3. Synthesis of tert-butyl(R)-5-(5-(tert-butyl)-1,2,4-oxadiazole-3-carboxamido)-8-(2-((1,5-dimethyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-1,3,4,5-tetrahydro-2H-benzo[c]azepine-2-carboxylate

A mixture of tert-butyl(R)-5-(5-(tert-butyl)-1,2,4-oxadiazole-3-carboxamido)-8-(2-chloropyrimidin-4-yl)-1,3,4,5-tetrahydro-2H-benzo[c]azepine-2-carboxylate(900 mg, 1.71 mmol), 1,5-dimethyl-1H-pyrazol-4-amine (228 mg, 2.05mmol), Cs₂CO₃ (1.11 g, 3.42 mmol), Pd₂(dba)₃ (157 mg, 0.17 mmol) andS-Phos (140 mg, 0.34 mmol) in 15 mL 1,4-dioxane was stirred at 100° C.for 2 h under nitrogen. The mixture was diluted with EtOAc (200 mL) andwashed with water (60 mL×2). The organic phase was dried with Na₂SO₄ andconcentrated. The crude product was purified by silica gelchromatography (DCM/MeOH=20:1) to give tert-butyl(R)-5-(5-(tert-butyl)-1,2,4-oxadiazole-3-carboxamido)-8-(2-((1,5-dimethyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-1,3,4,5-tetrahydro-2H-benzo[c]azepine-2-carboxylateas a yellow solid (110 mg, yield: 11%). ESI-MS (M+H)⁺: 602.3. ¹H NMR(400 MHz, CDCl₃) δ: 8.39-8.38 (m, 1H), 7.93-7.90 (m, 2H), 7.67 (s, 1H),7.46-7.44 (m, 2H), 7.05 (d, J=4.2 Hz, 1H), 6.48-6.41 (m, 1H), 5.69-5.59(m, 1H), 4.81-4.66 (m, 1H), 4.50-4.41 (m, 1H), 4.10-4.03 (m, 1H), 3.81(s, 3H), 3.61-3.52 (m, 1H), 2.23 (s, 3H), 2.20-2.16 (m, 2H), 1.40 (s,9H), 1.34-1.30 (m, 9H).

4. Synthesis of(R)-5-(tert-butyl)-N-(8-(2-((1,5-dimethyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1,2,4-oxadiazole-3-carboxamide

Synthesis of(R)-5-(tert-butyl)-N-(8-(2-((1,5-dimethyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1,2,4-oxadiazole-3-carboxamidewas like that of5-(tert-butyl)-N-(8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1,2,4-oxadiazole-3-carboxamidein Example 2. The crude material was carried forward without furtherpurification. ESI-MS (M+H)⁺: 502.2.

5. Synthesis of(R)-5-(tert-butyl)-N-(8-(2-((1,5-dimethyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(2-hydroxyethyl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1,2,4-oxadiazole-3-carboxamide

Synthesis of(R)-5-(tert-butyl)-N-(8-(2-((1,5-dimethyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(2-hydroxyethyl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1,2,4-oxadiazole-3-carboxamidewas similar to that of5-(tert-butyl)-N-(2-(2-hydroxyethyl)-8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1,2,4-oxadiazole-3-carboxamidein Example 3. The crude material was purified by silica gelchromatography (CH₂Cl₂:MeOH=10:1) to give(R)-5-(tert-butyl)-N-(8-(2-((1,5-dimethyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(2-hydroxyethyl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1,2,4-oxadiazole-3-carboxamideas a yellow solid (43 mg, yield 42%). ESI-MS (M+H)⁺: 546.3. ¹H NMR (400MHz, CD₃OD) δ: 8.32 (d, J=5.2 Hz, 1H), 8.00-7.98 (m, 2H), 7.60 (s, 1H),7.42 (d, J=8.0 Hz, 1H), 7.23 (d, J=5.2 Hz, 1H), 5.58-5.56 (m, 1H),4.16-4.10 (m, 2H), 3.82 (s, 3H), 3.73 (t, J=6.0 Hz, 2H), 3.30-3.21 (m,2H), 2.67-2.65 (m, 2H), 2.30-2.27 (m, 1H), 2.25 (s, 3H), 2.02-1.96 (m,1H), 1.52 (s, 9H).

Example 10.5-(tert-butyl)-N-(8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(tetrahydrofuran-3-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1,2,4-oxadiazole-3-carboxamide(compound 10)

Synthesis of5-(tert-butyl)-N-(8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(tetrahydrofuran-3-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1,2,4-oxadiazole-3-carboxamidewas similar to that described in Example 7, Step 3. The crude materialwas purified by prep-HPLC (CH₃CN/H₂O with 0.05% NH₄HCO₃ as mobile phase)to give5-(tert-butyl)-N-(8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(tetrahydrofuran-3-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1,2,4-oxadiazole-3-carboxamideas a yellow solid (97 mg, yield: 57%). ESI-MS (M+H)⁺: 558.3. ¹H NMR (400MHz, CD₃OD) δ: 8.43 (d, J=5.2 Hz, 1H), 8.04-7.99 (m, 3H), 7.64-7.63 (m,1H), 7.48 (d, J=8.0 Hz, 1H), 7.24 (d, J=5.2 Hz, 1H), 5.61 (d, J=9.6 Hz,1H), 4.10-3.91 (m, 4H), 3.90 (s, 3H), 3.78-3.71 (m, 2H), 3.36-3.10 (m,3H), 2.33-2.20 (m, 2H), 2.06-1.96 (m, 2H), 1.52 (s, 9H).

Example 11.(R)-5-(tert-butyl)-N-(8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(2,2,2-trifluoroethyl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1,2,4-oxadiazole-3-carboxamide(compound 11)

1. Synthesis of tert-butyl(R)-5-(5-(tert-butyl)-1,2,4-oxadiazole-3-carboxamido)-8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-1,3,4,5-tetrahydro-2H-benzo[c]azepine-2-carboxylate

Synthesis of tert-butyl(R)-5-(5-(tert-butyl)-1,2,4-oxadiazole-3-carboxamido)-8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-1,3,4,5-tetrahydro-2H-benzo[c]azepine-2-carboxylatewas similar to that of tert-butyl1-(5-(tert-butyl)-1,2,4-oxadiazole-3-carboxamido)-7-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-4,5-dihydro-1H-benzo[d]azepine-3(2H)-carboxylatein Example 1, Step 12. The crude material was purified by silica gelchromatography (EtOAc:MeOH=15:1) to give tert-butyl(R)-5-(5-(tert-butyl)-1,2,4-oxadiazole-3-carboxamido)-8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-1,3,4,5-tetrahydro-2H-benzo[c]azepine-2-carboxylateas a yellow solid (1.5 g, yield: 43%). ESI-MS (M+H)⁺: 588.3.

2. Synthesis of(R)-5-(tert-butyl)-N-(8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1,2,4-oxadiazole-3-carboxamide

To a solution of tert-butyl(R)-5-(5-(tert-butyl)-1,2,4-oxadiazole-3-carboxamido)-8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-1,3,4,5-tetrahydro-2H-benzo[c]azepine-2-carboxylate(1.4 g, 2.3 mmol) in CH₂Cl₂ (10 mL) was added TFA (10 mL). The mixturewas stirred for 1 h at room temperature. The reaction mixture wasconcentrated and the crude product (1.0 g, yield: 81%) was used in thenext step without further purification. ESI-MS (M+H)⁺: 488.3.

3. Synthesis of(R)-5-(tert-butyl)-N-(8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(2,2,2-trifluoroethyl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1,2,4-oxadiazole-3-carboxamide

To a solution of(R)-5-(tert-butyl)-N-(8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1,2,4-oxadiazole-3-carboxamide(75 mg, 0.15 mmol) in CH₃CN (5 mL) were added 2,2,2-trifluoroethyltrifluoromethanesulfonate (60 mg, 0.3 mmol) and DIPEA (34 mg, 0.3 mmol).The mixture was stirred at 80° C. for 2 h under microwave. The mixturewas concentrated and purified by prep-TLC (DCM/MeOH=10:1) to give(R)-5-(tert-butyl)-N-(8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(2,2,2-trifluoroethyl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1,2,4-oxadiazole-3-carboxamideas a yellow solid (45 mg, yield: 58%). ESI-MS (M+H)⁺: 570.2. ¹H NMR (400MHz, CD₃OD) δ: 8.30 (d, J=5.6 Hz, 1H), 7.92-7.86 (m, 3H), 7.50 (s, 1H),7.35 (d, J=8.0 Hz, 1H), 7.10 (d, J=5.6 Hz, 1H), 5.48-5.50 (m, 1H),4.26-4.22 (m, 1H), 4.02-3.98 (m, 1H), 3.78 (s, 3H), 3.32-3.27 (m, 1H),3.21-3.17 (m, 1H), 3.05-2.98 (m, 2H), 2.17-2.07 (m, 1H), 1.91-1.82 (m,1H), 1.40 (s, 9H).

Example 12.5-(tert-butyl)-N-(8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(tetrahydro-2H-pyran-4-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1,3,4-oxadiazole-2-carboxamide(compound 12)

1. The Preparation of tert-butyl8-bromo-5-(5-(tert-butyl)-1,3,4-oxadiazole-2-carboxamido)-4,5-dihydro-1H-benzo[c]azepine-2(3H)-carboxylate

To a solution of potassium 5-(tert-butyl)-1,3,4-oxadiazole-2-carboxylate(1.4 g, 6.7 mmol) and HATU (3.2 g, 8.4 mmol) in DMF (20 mL) were addedtriethylamine (1.69 g, 16.8 mmol) and tert-butyl5-amino-8-bromo-4,5-dihydro-1H-benzo[c]azepine-2(3H)-carboxylate (1.9 g,5.6 mmol). The mixture was stirred at rt for 4 h. After diluting withwater (80 mL), the mixture was extracted with EtOAc (100 mL×2). Thecombined organics were washed with brine (80 mL), dried, andconcentrated. The crude product was purified by silica gel columnchromatograph (PE/EtOAc=2:1) to give tert-butyl8-bromo-5-(5-(tert-butyl)-1,3,4-oxadiazole-2-carboxamido)-4,5-dihydro-1H-benzo[c]azepine-2(3H)-carboxylateas yellow solid (1.8 g, yield: 62%). ESI-MS (M+H-56)⁺: 437.3. ¹H NMR(400 MHz, CD₃OD) δ: 7.51-7.43 (m, 2H), 7.28-7.26 (m, 1H), 5.52-5.45 (m,1H), 4.65-4.61 (m, 1H), 4.43-4.39 (m, 1H), 4.15-4.09 (m, 1H), 3.65-3.43(m, 1H), 2.08-2.03 (m, 2H), 1.50 (s, 9H), 1.43-1.42 (m, 9H).

2. The Preparation of tert-butyl5-(5-(tert-butyl)-1,3,4-oxadiazole-2-carboxamido)-8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-4,5-dihydro-1H-benzo[c]azepine-2(3H)-carboxylate

A mixture of tert-butyl8-bromo-5-(5-(tert-butyl)-1,3,4-oxadiazole-2-carboxamido)-4,5-dihydro-1H-benzo[c]azepine-2(3H)-carboxylate(1.6 g, 3.2 mmol), PinB-BPin (802 mg, 3.84 mmol), KOAc (640 mg, 6.4mmol) and Pd(dppf)Cl₂.CH₂Cl₂ (130 mg, 0.16 mmol) in 20 mL dry1,4-dioxane was stirred at 80° C. for 16 h under nitrogen. After themixture was cooled to rt,4-chloro-N-(1-methyl-1H-pyrazol-4-yl)pyrimidin-2-amine (802 mg, 3.84mmol), Pd(dppf)Cl₂.CH₂Cl₂ (130 mg, 0.16 mmol), K₂CO₃(1.3 g, 9.6 mmol),and H₂O (5 mL) were added and the resulting mixture was stirred at 80°C. for another 16 h. The mixture was diluted with EtOAc (200 mL), washedwith water (80 mL×2), dried with Na₂SO₄, and concentrated. The crudeproduct was purified by silica gel column chromatography(EtOAc/MeOH=20:1) to give tert-butyl5-(5-(tert-butyl)-1,3,4-oxadiazole-2-carboxamido)-8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-4,5-dihydro-1H-benzo[c]azepine-2(3H)-carboxylateas yellow solid (1.4 g, yield: 86%). ESI-MS (M+H)⁺: 588.3. ¹H NMR (400MHz, CD₃OD) δ: 8.42-8.38 (m, 1H), 8.11-7.95 (m, 3H), 7.66-7.50 (m, 2H),7.24-7.21 (m, 1H), 5.64-5.62 (m, 1H), 4.85-4.47 (m, 2H), 3.93-3.88 (m,1H), 3.57-3.54 (m, 1H), 2.12-2.10 (m, 2H), 1.51 (s, 9H), 1.43-1.34 (m,9H)

3. The Preparation of5-(tert-butyl)-N-(8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1,3,4-oxadiazole-2-carboxamide

To a solution of tert-butyl5-(5-(tert-butyl)-1,3,4-oxadiazole-2-carboxamido)-8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-4,5-dihydro-1H-benzo[c]azepine-2(3H)-carboxylate(600 mg, 1.02 mmol) in CH₂Cl₂ (5 mL) was added TFA (5 mL). The mixturewas stirred 1 h at rt. After removal of the solvent, the residue wasdried in vacuo to give crude title product (460 mg, yield: 80%), whichwas used in the next step without further purification. ESI-MS (M+H)⁺:488.3.

4. Synthesis of5-(tert-butyl)-N-(8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(tetrahydro-2H-pyran-4-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1,3,4-oxadiazole-2-carboxamide

To a solution of5-(tert-butyl)-N-(8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1,3,4-oxadiazole-2-carboxamide(170 mg, 0.35 mmol) and dihydro-pyran-4-one (175 mg, 1.75 mmol) in MeOH(30 mL) were added NaBH₃CN (112 mg, 1.75 mmol) and CH₃COOH (cat). Themixture was stirred at 50° C. for 4 h. After cooling to rt, the mixturewas adjusted to pH=8 with conc. NH₄OH. After concentration, the crudeproduct was purified by prep-HPLC (CH₃CN/H₂O with 0.05% NH₄HCO₃ asmobile phase) to give5-(tert-butyl)-N-(8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(tetrahydro-2H-pyran-4-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1,3,4-oxadiazole-2-carboxamideas a yellow solid (24 mg, yield: 9%). ESI-MS (M+H)⁺: 572.3. ¹H NMR (400MHz, CD₃OD) δ: 8.29 (d, J=5.2 Hz, 1H), 7.91-7.85 (m, 3H), 7.53 (s, 1H),7.36 (d, J=8.0 Hz, 1H), 7.10 (d, J=5.6 Hz, 1H), 5.44 (d, J=9.2 Hz, 1H),4.08-3.86 (m, 4H), 3.78 (s, 3H), 3.28-3.20 (m, 3H), 3.08-3.01 (m, 1H),2.63-2.57 (m, 1H), 2.14-2.09 (m, 1H), 1.94-1.76 (m, 3H), 1.63-1.49 (m,2H), 1.38 (s, 9H).

Example 13.5-(tert-butyl)-N-(8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(oxetan-3-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1,3,4-oxadiazole-2-carboxamide(compound 13)

Synthesis of5-(tert-butyl)-N-(8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(oxetan-3-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1,3,4-oxadiazole-2-carboxamidewas similar to that of5-(tert-butyl)-N-(8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(tetrahydro-2H-pyran-4-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1,2,4-oxadiazole-3-carboxamidein Example 8. The crude product was purified by prep-HPLC (CH₃CN/H₂Owith 0.05% NH₄HCO₃ as mobile phase) to give5-(tert-butyl)-N-(8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(oxetan-3-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1,3,4-oxadiazole-2-carboxamideas a yellow solid (59 mg, yield: 33%). ESI-MS (M+H)⁺: 544.2. ¹H NMR (400MHz, CD₃OD) δ: 8.29 (d, J=5.2 Hz, 1H), 7.91 (d, J=8.0 Hz, 1H), 7.86 (s,1H), 7.83 (s, 1H), 7.51 (s, 1H), 7.36 (d, J=8.4 Hz, 1H), 7.09 (d, J=5.2Hz, 1H), 5.46 (d, J=10.0 Hz, 1H), 4.65-5.55 (m, 4H), 3.83-3.67 (m, 3H),3.77 (s, 3H), 2.96-2.93 (m, 1H), 2.79-2.73 (m, 1H), 2.13-2.10 (m, 1H),1.93-1.90 (m, 1H), 1.38 (s, 9H).

Example 14.(R)-5-(tert-butyl)-N-(8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(oxetan-3-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1,3,4-oxadiazole-2-carboxamide(compound 14a) and(S)-5-(tert-butyl)-N-(8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(oxetan-3-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1,3,4-oxadiazole-2-carboxamide(compound 14b) Method 1

5-tert-Butyl-1,3,4-oxadiazole-2-carboxylic acid{8-[2-(1-methyl-1H-pyrazol-4-ylamino)-pyrimidin-4-yl]-2-oxetan-3-yl-2,3,4,5-tetrahydro-1H-2-benzazepin-5-yl}-amide(264 mg) was subjected to SFC separation (OD-H (2×25 cm), 30% methanol(0.1% DEA)/CO₂, 100 bar, 65 mL/min, 220 nm, inj vol.: 0.5 mL, 4 mg/mL,methanol) and yielded 93 mg of peak-1 (chemical purity>99%, ee>99%) and97 mg of peak-2 (chemical purity>99%, ee>99%).

Peak 1 was assigned as 5-tert-butyl-1,3,4-oxadiazole-2-carboxylic acid{(R)-8-[2-(1-methyl-1H-pyrazol-4-ylamino)-pyrimidin-4-yl]-2-oxetan-3-yl-2,3,4,5-tetrahydro-1H-2-benzazepin-5-yl}-amide:LCMS: Rt 0.84 min, m/z 544.2. ¹H NMR (400 MHz, METHANOL-d₄) δ 8.41 (br.s., 1H), 7.84-8.14 (m, 3H), 7.63 (br. s., 1H), 7.47 (t, J=7.56 Hz, 1H),7.21 (d, J=10.04 Hz, 1H), 5.57 (d, J=9.29 Hz, 1H), 4.61-4.80 (m, 4H),3.66-4.07 (m, 6H), 3.05 (br. s., 1H), 2.88 (d, J=9.04 Hz, 1H), 2.23 (br.s., 1H), 2.05 (br. s., 1H), 1.50 (d, J=2.89 Hz, 9H).

Peak 2 was assigned as 5-tert-butyl-1,3,4-oxadiazole-2-carboxylic acid{(S)-8-[2-(1-methyl-1H-pyrazol-4-ylamino)-pyrimidin-4-yl]-2-oxetan-3-yl-2,3,4,5-tetrahydro-1H-2-benzazepin-5-yl}-amide:LCMS: Rt 0.84 min, m/z 544.2. ¹H NMR (400 MHz, METHANOL-d₄) δ 8.42 (d,J=5.02 Hz, 1H), 7.86-8.14 (m, 3H), 7.63 (s, 1H), 7.48 (d, J=8.09 Hz,1H), 7.22 (d, J=5.27 Hz, 1H), 5.58 (d, J=9.73 Hz, 1H), 4.59-4.81 (m,4H), 3.73-4.05 (m, 6H), 3.05 (br. s., 1H), 2.89 (br. s., 1H), 2.23 (br.s., 1H), 2.06 (d, J=5.52 Hz, 1H), 1.50 (s, 9H).

Method 2 1. Synthesis of tert-butyl(R)-8-bromo-5-(5-(tert-butyl)-1,3,4-oxadiazole-2-carboxamido)-1,3,4,5-tetrahydro-2H-benzo[c]azepine-2-carboxylate

To a solution of tert-butyl(R)-5-amino-8-bromo-1,3,4,5-tetrahydro-2H-benzo[c]azepine-2-carboxylate(3.1 g, 4.5 mmol) and triethylamine (910 mg, 9.0 mmol) in DCM (100 mL)were added HATU (2.6 g, 6.8 mmol) and potassium5-(tert-butyl)-1,3,4-oxadiazole-2-carboxylate (1.12 g, 5.4 mmol). Themixture was stirred at rt for 2 h. Then water (100 mL) was added and themixture was extracted with DCM (2×100 mL). The combined organics weredried and concentrated. The crude product was purified by silica gelcolumn chromatography (petroleum ether/EtOAc=4:1) to give tert-butyl(R)-8-bromo-5-(5-(tert-butyl)-1,3,4-oxadiazole-2-carboxamido)-1,3,4,5-tetrahydro-2H-benzo[c]azepine-2-carboxylateas white solid (1.8 g, yield: 82%). ESI-MS (M+H)⁺: 493.1.

2. Synthesis of tert-butyl(R)-5-(5-(tert-butyl)-1,3,4-oxadiazole-2-carboxamido)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,4,5-tetrahydro-2H-benzo[c]azepine-2-carboxylate

A mixture of tert-butyl(R)-8-bromo-5-(5-(tert-butyl)-1,3,4-oxadiazole-2-carboxamido)-1,3,4,5-tetrahydro-2H-benzo[c]azepine-2-carboxylate(1.8 g, 3.65 mmol), bis(pinocolato)diboron (975 mg, 3.84 mmol), KOAc(715 mg, 7.30 mmol) and Pd(dppf)Cl₂.DCM (293 mg, 0.36 mmol) in 30 mL1,4-dioxane was stirred at 90° C. for 2 h under nitrogen. After coolingto rt, the mixture was diluted with EtOAc (200 mL), washed with water(2×50 mL), dried with Na₂SO₄ and concentrated. The crude producttert-butyl(R)-5-(5-(tert-butyl)-1,3,4-oxadiazole-2-carboxamido)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,4,5-tetrahydro-2H-benzo[c]azepine-2-carboxylatewas used for next step without purification. ESI-MS (M+H)⁺: 541.3.

3. Synthesis of tert-butyl(R)-5-(5-(tert-butyl)-1,3,4-oxadiazole-2-carboxamido)-8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-1,3,4,5-tetrahydro-2H-benzo[c]azepine-2-carboxylate

A mixture of tert-butyl(R)-5-(5-(tert-butyl)-1,3,4-oxadiazole-2-carboxamido)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,4,5-tetrahydro-2H-benzo[c]azepine-2-carboxylate(4.85 g, 8.98 mmol),4-chloro-N-(1-methyl-1H-pyrazol-4-yl)pyrimidin-2-amine (1.88 g, 8.98mmol), Pd(dppf)Cl₂ (734 mg, 0.9 mmol) and K₂CO₃ (2.48 g, 18 mmol) indioxane/H₂O (4:1, 20 mL) was degassed and stirred at 100° C. for 2 hunder a N₂ atmosphere. After concentration of the reaction mixture, theresidue was purified by silica-gel chromatography (EtOAc:PE=2:1) to givetert-butyl(R)-5-(5-(tert-butyl)-1,3,4-oxadiazole-2-carboxamido)-8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-1,3,4,5-tetrahydro-2H-benzo[c]azepine-2-carboxylateas a yellow solid (3.4 g, yield: 51%). ESI-MS (M+H)⁺: 588.3.

4. Synthesis of(R)-5-(tert-butyl)-N-(8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1,3,4-oxadiazole-2-carboxamide

To a solution of tert-butyl(R)-5-(5-(tert-butyl)-1,3,4-oxadiazole-2-carboxamido)-8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-1,3,4,5-tetrahydro-2H-benzo[c]azepine-2-carboxylate(3.4 g, 5.79 mmol) in DCM (10 mL) was added TFA (4 mL). The resultingsolution was stirred at room temperature for 2 h. After concentration ofthe reaction mixture, the residue was dissolved in MeOH (10 mL) andadjusted to pH=8 with aqueous ammonia. Then water (20 mL) was added andthe mixture was extracted with DCM/MeOH solutions (20:1, 30 mL×3). Theorganic phase was dried and concentrated to give crude(R)-5-(tert-butyl)-N-(8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1,3,4-oxadiazole-2-carboxamideas a yellow solid (2.47 g, yield: 88%), which was used to next stepwithout further purification. ESI-MS (M+H)⁺: 488.2.

5. Synthesis of(R)-5-(tert-butyl)-N-(8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(oxetan-3-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1,3,4-oxadiazole-2-carboxamide(I-RP38)

To a solution of(R)-5-(tert-butyl)-N-(8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1,3,4-oxadiazole-2-carboxamide(1.5 g, 3.08 mmol) and oxetan-3-one (1.1 g, 15.4 mmol) in MeOH (30 mL)was added NaBH₃CN (970 mg, 15.4 mmol) and ZnCl₂ (4.2 g, 30.8 mmol). Theresulting mixture was stirred at room temperature for 4 h. Afterdiluting with H₂O (20 mL), the mixture was extracted with DCM/MeOHsolutions (20:1, 20 mL×3). The combined organic layers were dried andconcentrated. The residue was purified by silica-gel chromatography(DCM:MeOH=50:1 to 20:1) to give(R)-5-(tert-butyl)-N-(8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(oxetan-3-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1,3,4-oxadiazole-2-carboxamideas a yellow solid (1.1 g, yield: 58%). ESI-MS (M+H)⁺: 544.3. ¹H NMR (400MHz, CDCl₃) δ: 8.42 (d, J=5.2 Hz, 1H), 8.32 (br, 1H), 7.86-7.78 (m, 3H),7.53-7.26 (m, 2H), 7.15 (s, 1H), 7.05-7.03 (m, 1H), 5.62 (t, J=8.4 Hz,1H), 4.75-4.67 (m, 4H), 3.94-3.85 (m, 6H), 3.02-2.96 (m, 1H), 2.75-2.70(m, 1H), 2.35-2.31 (m, 1H), 2.14-2.07 (m, 1H), 1.47 (s, 9H).

Example 15.5-(tert-butyl)-N-(8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(methylsulfonyl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1,3,4-oxadiazole-2-carboxamide(compound 15)

To a solution of5-(tert-butyl)-N-(8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1,3,4-oxadiazole-2-carboxamide(100 mg, 0.20 mmol) in CH₂Cl₂ (20 mL) were added MsCl (34 mg, 0.3 mmol)and triethylamine (61 mg, 0.60 mmol). The mixture was stirred at rt for2 h. The mixture was diluted with CH₂Cl₂ (100 mL), washed with brine (60mL), and concentrated. The crude product was purified by prep-HPLC(CH₃CN/H₂O with 0.05% NH₄HCO₃ as mobile phase) to give5-(tert-butyl)-N-(8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(methylsulfonyl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1,3,4-oxadiazole-2-carboxamideas a yellow solid (130 mg, yield: 87%). ESI-MS (M+H)⁺: 566.3. ¹H NMR(400 MHz, DMSO-d₆) δ: 10.01 (d, J=7.6 Hz, 1H), 9.57 (s, 1H), 8.49 (d,J=5.2 Hz, 1H), 8.07 (s, 1H), 8.04 (d, J=8.4 Hz, 1H), 7.99 (br, 1H), 7.50(s, 1H), 7.47 (d, J=8.4 Hz, 1H), 7.27 (d, J=5.2 Hz, 1H), 5.56-5.51 (m,1H), 4.75-4.70 (m, 1H), 4.60-4.56 (m, 1H), 3.86-3.84 (m, 1H), 3.83 (s,3H), 3.61-3.58 (m, 1H), 2.80 (s, 3H), 2.15-2.09 (m, 2H), 1.43 (s, 9H).

Example 16.(R)-5-(tert-butyl)-N-(2-(2-hydroxyethyl)-8-(2-((1-isopropyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1,3,4-oxadiazole-2-carboxamide(compound 16)

1. Synthesis of tert-butyl(R)-8-bromo-5-(5-(tert-butyl)-1,3,4-oxadiazole-2-carboxamido)-1,3,4,5-tetrahydro-2H-benzo[c]azepine-2-carboxylate

To a solution of tert-butyl(R)-5-amino-8-bromo-1,3,4,5-tetrahydro-2H-benzo[c]azepine-2-carboxylate(3.1 g, 4.5 mmol) and triethylamine (910 mg, 9.0 mmol) in DCM (100 mL)were added HATU (2.6 g, 6.8 mmol) and potassium5-(tert-butyl)-1,3,4-oxadiazole-2-carboxylate (1.12 g, 5.4 mmol). Themixture was stirred at rt for 2 h. Then water (100 mL) was added and themixture was extracted with DCM (2×100 mL). The combined organics weredried and concentrated. The crude product was purified by silica gelcolumn chromatography (petroleum ether/EtOAc=4:1) to give tert-butyl(R)-8-bromo-5-(5-(tert-butyl)-1,3,4-oxadiazole-2-carboxamido)-1,3,4,5-tetrahydro-2H-benzo[c]azepine-2-carboxylateas white solid (1.8 g, yield: 82%). ESI-MS (M+H)⁺: 493.1.

2. Synthesis of tert-butyl(R)-5-(5-(tert-butyl)-1,3,4-oxadiazole-2-carboxamido)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,4,5-tetrahydro-2H-benzo[c]azepine-2-carboxylate

A mixture of tert-butyl(R)-8-bromo-5-(5-(tert-butyl)-1,3,4-oxadiazole-2-carboxamido)-1,3,4,5-tetrahydro-2H-benzo[c]azepine-2-carboxylate(1.8 g, 3.65 mmol), bis(pinocolato)diboron (975 mg, 3.84 mmol), KOAc(715 mg, 7.30 mmol) and Pd(dppf)Cl₂.DCM (293 mg, 0.36 mmol) in 30 mL1,4-dioxane was stirred at 90° C. for 2 h under nitrogen. After coolingto rt, the mixture was diluted with EtOAc (200 mL), washed with water(2×50 mL), dried with Na₂SO₄ and concentrated.

The crude product tert-butyl(R)-5-(5-(tert-butyl)-1,3,4-oxadiazole-2-carboxamido)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,4,5-tetrahydro-2H-benzo[c]azepine-2-carboxylatewas used for next step without purification. ESI-MS (M+H)⁺: 541.3.

3. Synthesis of tert-butyl(R)-5-(5-(tert-butyl)-1,3,4-oxadiazole-2-carboxamido)-8-(2-chloropyrimidin-4-yl)-1,3,4,5-tetrahydro-2H-benzo[c]azepine-2-carboxylate

A mixture of tert-butyl(R)-5-(5-(tert-butyl)-1,3,4-oxadiazole-2-carboxamido)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,4,5-tetrahydro-2H-benzo[c]azepine-2-carboxylate,2,4-dichloropyrimidine (648 mg, 4.38 mmol), K₂CO₃ (1.0 g, 7.30 mmol) andPd(dppf)Cl₂.DCM (293 mg, 0.36 mmol) in 30 mL 1,4-dioxane and 6 mL waterwas stirred at 90° C. for 12 h under nitrogen. The mixture was dilutewith EtOAc (200 mL) and washed with water (2×60 mL). The organic phasewas dried with Na₂SO₄ and concentrated. The crude product was purifiedby silica gel column chromatography (DCM/MeOH=20:1) to give tert-butyl(R)-5-(5-(tert-butyl)-1,3,4-oxadiazole-2-carboxamido)-8-(2-chloropyrimidin-4-yl)-1,3,4,5-tetrahydro-2H-benzo[c]azepine-2-carboxylateas a yellow solid (1.3 g, yield: 67% for two steps). ESI-MS (M+H)⁺:527.2.

4. Synthesis of tert-butyl(R)-5-(5-(tert-butyl)-1,3,4-oxadiazole-2-carboxamido)-8-(2-((1-isopropyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-1,3,4,5-tetrahydro-2H-benzo[c]azepine-2-carboxylate

Synthesis of tert-butyl(R)-5-(5-(tert-butyl)-1,3,4-oxadiazole-2-carboxamido)-8-(2-((1-isopropyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-1,3,4,5-tetrahydro-2H-benzo[c]azepine-2-carboxylatewas similar to that of tert-butyl(R)-5-(5-(tert-butyl)-1,2,4-oxadiazole-3-carboxamido)-8-(2-((1,5-dimethyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-1,3,4,5-tetrahydro-2H-benzo[c]azepine-2-carboxylate(Example 9, Step 3). The crude product was purified by silica gel columnchromatography (EtOAc/petroleum ether=3:1) to give tert-butyl(R)-5-(5-(tert-butyl)-1,3,4-oxadiazole-2-carboxamido)-8-(2-((1-isopropyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-1,3,4,5-tetrahydro-2H-benzo[c]azepine-2-carboxylateas a yellow solid (280 mg, yield: 78%). ESI-MS (M+H)⁺: 616.3.

5. Synthesis of(R)-5-(tert-butyl)-N-(8-(2-((1-isopropyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1,3,4-oxadiazole-2-carboxamide

Synthesis of(R)-5-(tert-butyl)-N-(8-(2-((1-isopropyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1,3,4-oxadiazole-2-carboxamidewas similar to that of(R)-5-(tert-butyl)-N-(8-(2-((1,5-dimethyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1,2,4-oxadiazole-3-carboxamide(Example 9, Step 4). Crude(R)-5-(tert-butyl)-N-(8-(2-((1-isopropyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1,3,4-oxadiazole-2-carboxamideas yellow solid (240 mg) was used to next step without furtherpurification. ESI-MS (M+H)⁺: 516.3.

6. Synthesis of(R)-5-(tert-butyl)-N-(2-(2-hydroxyethyl)-8-(2-((1-isopropyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1,3,4-oxadiazole-2-carboxamide

To a solution of(R)-5-(tert-butyl)-N-(8-(2-((1-isopropyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1,3,4-oxadiazole-2-carboxamide(240 mg, 0.47 mmol) and 2-iodoethanol (200 mg, 1.17 mmol) in 10 mL ofCH₃CN was added K₂CO₃ (195 mg, 1.41 mmol). The resulting mixture wasstirred at 80° C. for 24 h. After diluting with H₂O (20 mL), the mixturewas extracted with DCM/MeOH solutions (20:1, 3×40 mL). The combinedorganic layers were dried (Na₂SO₄) and concentrated. The residue waspurified by prep-TLC (DCM/MeOH=10:1) to give(R)-5-(tert-butyl)-N-(2-(2-hydroxyethyl)-8-(2-((1-isopropyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1,3,4-oxadiazole-2-carboxamideas a yellow solid (108 mg, yield: 42%). ESI-MS (M+H)⁺: 560.3. ¹H NMR(400 MHz, CD₃OD) δ: 8.37 (d, J=5.2 Hz, 1H), 8.03 (s, 1H), 7.98-7.95 (m,2H), 7.66 (s, 1H), 7.44 (d, J=8.4 Hz, 1H), 7.17 (d, J=5.2 Hz, 1H), 5.55(d, J=9.6 Hz, 1H), 4.54-4.37 (m, 1H), 4.17-4.04 (m, 2H), 3.71 (t, J=6.0Hz, 2H), 3.30-3.17 (m, 2H), 2.29-2.25 (m, 2H), 2.29-2.25 (m, 1H),1.99-1.95 (m, 1H), 1.52 (d, J=6.4 Hz, 6H), 1.49 (s, 9H).

Example 17.(R)-5-(tert-butyl)-N-(8-(2-((1-isopropyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(oxetan-3-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1,3,4-oxadiazole-2-carboxamide(compound 17)

A mixture of(R)-5-(tert-butyl)-N-(8-(2-((1-isopropyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1,3,4-oxadiazole-2-carboxamide(220 mg, 0.43 mmol), oxetan-3-one (157 mg, 2.15 mmol), NaBH₃CN (135 mg,2.15 mmol) and ZnCl₂ (585 mg, 4.30 mmol) in 10 mL MeOH was stirred at rtfor 16 h. The mixture was dilute with EtOAc (150 mL) and washed withwater (50 mL×2). The organic phase was dried with Na₂SO₄ andconcentrated. The crude product was purified by silica gelchromatography (DCM:MeOH=15:1) to give(R)-5-(tert-butyl)-N-(8-(2-((1-isopropyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(oxetan-3-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1,3,4-oxadiazole-2-carboxamideas a yellow solid (146 mg, yield: 60%). ESI-MS (M+H)⁺: 572.3. ¹H NMR(400 MHz, CDCl₃) δ: 8.42 (d, J=5.2 Hz, 1H), 8.05-7.97 (m, 3H), 7.67 (s,1H), 7.48 (d, J=8.0 Hz, 1H), 7.22 (d, J=8.4 Hz, 1H), 5.59-5.57 (m, 1H),4.87-4.66 (m, 4H), 4.53-4.50 (m, 1H), 3.98-3.81 (m, 3H), 3.09-3.03 (m,1H), 2.92-2.86 (m, 1H), 2.29-2.20 (m, 1H), 2.07-2.03 (m, 1H), 1.54-1.51(m, 15H)

Example 18.(R)-5-(tert-butyl)-N-(8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(2,2,2-trifluoroethyl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1,3,4-oxadiazole-2-carboxamide(compound 18)

1. Synthesis of tert-butyl(R)-5-(5-(tert-butyl)-1,3,4-oxadiazole-2-carboxamido)-8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-1,3,4,5-tetrahydro-2H-benzo[c]azepine-2-carboxylate

A mixture of tert-butyl(R)-5-(5-(tert-butyl)-1,3,4-oxadiazole-2-carboxamido)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,4,5-tetrahydro-2H-benzo[c]azepine-2-carboxylate(4.85 g, 8.98 mmol),4-chloro-N-(1-methyl-1H-pyrazol-4-yl)pyrimidin-2-amine (1.88 g, 8.98mmol), Pd(dppf)Cl₂ (734 mg, 0.9 mmol) and K₂CO₃ (2.48 g, 18 mmol) indioxane/H₂O (4:1, 20 mL) was degassed and stirred at 100° C. for 2 hunder a N₂ atmosphere. After concentration of the reaction mixture, theresidue was purified by silica-gel chromatography (EtOAc:PE=2:1) to givetert-butyl(R)-5-(5-(tert-butyl)-1,3,4-oxadiazole-2-carboxamido)-8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-1,3,4,5-tetrahydro-2H-benzo[c]azepine-2-carboxylateas a yellow solid (3.4 g, yield: 51%). ESI-MS (M+H)⁺: 588.3.

2. Synthesis of(R)-5-(tert-butyl)-N-(8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1,3,4-oxadiazole-2-carboxamide

To a solution of tert-butyl(R)-5-(5-(tert-butyl)-1,3,4-oxadiazole-2-carboxamido)-8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-1,3,4,5-tetrahydro-2H-benzo[c]azepine-2-carboxylate(3.4 g, 5.79 mmol) in DCM (10 mL) was added TFA (4 mL). The resultingsolution was stirred at room temperature for 2 h. After concentration ofthe reaction mixture, the residue was dissolved in MeOH (10 mL) andadjusted to pH=8 with aqueous ammonia. Then water (20 mL) was added andthe mixture was extracted with DCM/MeOH solutions (20:1, 30 mL×3). Theorganic phase was dried and concentrated to give crude(R)-5-(tert-butyl)-N-(8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1,3,4-oxadiazole-2-carboxamideas a yellow solid (2.47 g, yield: 88%), which was used to next stepwithout further purification. ESI-MS (M+H)⁺: 488.2.

3. Synthesis of(R)-5-(tert-butyl)-N-(8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(2,2,2-trifluoroethyl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1,3,4-oxadiazole-2-carboxamide

To a solution of(R)-5-(tert-butyl)-N-(8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1,3,4-oxadiazole-2-carboxamide(1.5 g, 3.1 mmol) and DIPEA (800 mg, 6.2 mmol) in CH₃CN (30 mL) wasadded 2,2,2-trifluoroethyl trifluoromethanesulfonate (1.1 g, 4.7 mmol).The mixture was stirred at 50° C. for 12 h. After diluting with water(100 mL), the mixture was extracted with DCM (100 mL×3). The combinedorganic layers were washed with brine (100 mL), dried (Na₂SO₄), filteredand concentrated. The crude product was purified by silica gelchromatography (DCM:MeOH=10:1) to give(R)-5-(tert-butyl)-N-(8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(2,2,2-trifluoroethyl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1,3,4-oxadiazole-2-carboxamideas a yellow solid (1.2 g, yield: 68%). ESI-MS (M+H)⁺: 570.2. ¹H NMR (400MHz, CD₃OD) δ: 8.31 (d, J=5.2 Hz, 1H), 7.94-7.88 (m, 3H), 7.51 (s, 1H),7.38 (d, J=8.0 Hz, 1H), 7.12 (d, J=5.2 Hz, 1H), 5.49-5.47 (m, 1H),4.27-4.23 (m, 1H), 4.04-4.00 (m, 1H), 3.78 (s, 3H), 3.33-3.24 (m, 2H),3.04-2.98 (m, 2H), 2.14-2.05 (m, 1H), 1.87-1.84 (m, 1H), 1.40 (s, 9H).

Example 19.5-(tert-butyl)-N-(2-(2-hydroxyethyl)-8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1,3,4-oxadiazole-2-carboxamide(compound 19)

Synthesis of5-(tert-butyl)-N-(2-(2-hydroxyethyl)-8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1,3,4-oxadiazole-2-carboxamidewas similar to that of5-(tert-butyl)-N-(2-(2-hydroxyethyl)-8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1,2,4-oxadiazole-3-carboxamidein Example 3. The crude product was purified by prep-HPLC (CH₃CN/H₂Owith 0.05% NH₄HCO₃ as mobile phase) to give5-(tert-butyl)-N-(2-(2-hydroxyethyl)-8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1,3,4-oxadiazole-2-carboxamideas a yellow solid (165 mg, yield: 84%). ESI-MS (M+H)⁺: 532.2. ¹H NMR(400 MHz, CD₃OD) δ: 8.42 (d, J=5.2 Hz, 1H), 8.03-8.00 (m, 3H), 7.64 (s,1H), 7.48 (d, J=8.0 Hz, 1H), 7.23-7.22 (m, 1H), 5.58 (d, J=9.6 Hz, 1H),4.21-4.09 (m, 2H), 3.90 (s, 3H), 3.74 (t, J=5.6 Hz, 2H), 3.20-3.18 (m,2H), 2.70-2.62 (m, 2H), 2.30-2.28 (m, 1H), 2.00-1.98 (m, 1H), 1.52 (s,9H).

Example 20.5-(tert-butyl)-N—((R)-8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-((R)-tetrahydrofuran-3-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1,3,4-oxadiazole-2-carboxamide(compound 20)

1. Synthesis of (S)-tetrahydrofuran-3-yl trifluoromethanesulfonate

To a solution of (S)-tetrahydrofuran-3-ol (500 mg, 5.7 mmol) andpyridine (538 mg, 6.8 mmol) in DCM (15 mL) at −10° C. was added Tf₂O(1.8 g, 6.3 mmol). The mixture was stirred at −10° C. for 0.5 h. Themixture was quenched with 2N HCl solution. The organic layer wereseparated, dried over Na₂SO₄ and filtered. The resulting DCM solution of(S)-tetrahydrofuran-3-yl trifluoromethanesulfonate was used for nextstep. ESI-MS (M+H)⁺: 221.0.

2. Synthesis of5-(tert-butyl)-N—((R)-8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-((R)-tetrahydrofuran-3-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1,3,4-oxadiazole-2-carboxamide

To a solution of(R)-5-(tert-butyl)-N-(8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1,3,4-oxadiazole-2-carboxamide(1.7 g, 3.5 mmol) in THF (24 mL) and DMF (3 mL) was added KHMDS (5.2 mL,5.2 mmol, 1M solution) dropwise at −78° C. The solution was stirredunder nitrogen at −78° C. for 0.5 h. Then, the solution of(S)-tetrahydrofuran-3-yl trifluoromethanesulfonate (from previous step)was added dropwise. The mixture was stirred at room temperature for 16h. After diluting with water (40 mL), the mixture was extracted with DCM(40 mL×3). The combined organic layers were washed with brine (60 mL),dried (Na₂SO₄), filtered and concentrated. The crude product waspurified by silica gel chromatography (DCM:MeOH=10:1) to give5-(tert-butyl)-N—((R)-8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-((R)-tetrahydrofuran-3-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1,3,4-oxadiazole-2-carboxamideas a yellow solid (448 mg, yield: 23%). ESI-MS (M+H)⁺: 558.3. ¹H NMR(400 MHz, DMSO-d₆) δ: 9.82-9.80 (m, 1H), 9.51 (s, 1H), 8.47 (d, J=4.8Hz, 1H), 7.99-7.95 (m, 3H), 7.55 (s, 1H), 7.40 (d, J=8.0 Hz, 1H), 7.28(d, J=5.2 Hz, 1H), 5.43-5.38 (m, 1H), 4.06-3.99 (m, 2H), 3.83-380 (m,5H), 3.63-3.50 (m, 2H), 3.10-3.05 (m, 3H), 2.22-2.02 (m, 2H), 1.85-1.82(m, 2H), 1.42 (s, 9H).

Example 21.5-(tert-butyl)-N—((R)-2-((S)-2-hydroxypropyl)-8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1,3,4-oxadiazole-2-carboxamide(compound 21)

To a solution of(R)-5-(tert-butyl)-N-(8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1,3,4-oxadiazole-2-carboxamide(101 mg, 0.21 mmol) in MeOH (7 mL) was added (S)-2-methyloxirane (29 μL,0.42 mmol) and cesium carbonate (135 mg, 0.42 mmol). The mixture wasstirred at 60° C. for 16 h. The reaction mixture was cooled to roomtemperature and filtered. The filtrate was concentrated and the crudeproduct was purified by silica gel chromatography (DCM:MeOH=10:1) togive5-(tert-butyl)-N—((R)-2-((S)-2-hydroxypropyl)-8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1,3,4-oxadiazole-2-carboxamideas a yellow solid (50 mg, yield: 44%). ESI-MS (M+H)⁺: 546.0. ¹H NMR (400MHz, METHANOL-d₄) δ: 8.41 (d, J=5.3 Hz, 1H), 8.07-8.02 (m, 2H), 7.97 (s,1H), 7.63 (s, 1H), 7.48 (d, J=8.5 Hz, 1H), 7.22 (d, J=5.3 Hz, 1H),5.62-5.53 (m, 1H), 4.33-4.10 (m, 2H), 4.04-3.95 (m, 1H), 3.89 (s, 3H),3.33-3.27 (m, 2H), 2.58-2.46 (m, 2H), 2.38-2.23 (m, 1H), 2.07-1.95 (m,1H), 1.48 (s, 9H), 1.15 (d, J=6.3 Hz, 3H).

Example 22.5-(tert-butyl)-N—((R)-8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-((S)-tetrahydrofuran-3-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1,3,4-oxadiazole-2-carboxamide(compound 22)

1. Synthesis of (R)-tetrahydrofuran-3-yl trifluoromethanesulfonate

Synthesis of (R)-tetrahydrofuran-3-yl trifluoromethanesulfonate) wassimilar to that of (S)-tetrahydrofuran-3-yl trifluoromethanesulfonate)in Example 20, Step 1. The resulting DCM solution was used for the nextstep. ESI-MS (M+H)⁺: 221.0.

2. Synthesis of5-(tert-butyl)-N—((R)-8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-((S)-tetrahydrofuran-3-yl)-2,3,4,5-tetrahydro-H-benzo[c]azepin-5-yl)-1,3,4-oxadiazole-2-carboxamide(I-RP58)

Synthesis of5-(tert-butyl)-N—((R)-8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-((S)-tetrahydrofuran-3-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1,3,4-oxadiazole-2-carboxamidewas similar to that of5-(tert-butyl)-N—((R)-8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-((R)-tetrahydrofuran-3-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1,3,4-oxadiazole-2-carboxamidein Example 20, Step 2. The crude product was purified by silica gelchromatography (DCM:MeOH=10:1) to give5-(tert-butyl)-N—((R)-8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-((S)-tetrahydrofuran-3-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1,3,4-oxadiazole-2-carboxamideas a yellow solid (50 mg, yield: 38%). ESI-MS (M+H)⁺: 558.1. ¹H NMR (400MHz, METHANOL-d₄) δ: 8.38 (d, J=5.3 Hz, 1H), 8.03-7.95 (m, 3H), 7.60 (s,1H), 7.45 (d, J=8.5 Hz, 1H), 7.19 (d, J=5.3 Hz, 1H), 5.56 (br d, J=9.3Hz, 1H), 4.12-4.01 (m, 2H), 4.01-3.90 (m, 2H), 3.88 (s, 3H), 3.79-3.68(m, 2H), 3.29-3.21 (m, 1H), 3.20-3.09 (m, 1H), 2.33-2.11 (m, 2H),2.09-1.90 (m, 2H), 1.48 (s, 9H).

Example 23.1-(tert-butyl)-N-(8-(2-((1-ethyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(oxetan-3-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1H-1,2,3-triazole-4-carboxamide(compound 23)

1. The Preparation of tert-butyl8-bromo-5-(1-(tert-butyl)-1H-1,2,3-triazole-4-carboxamido)-1,3,4,5-tetrahydro-2H-benzo[c]azepine-2-carboxylate

To a solution of tert-butyl8-bromo-5-(1-(tert-butyl)-1H-1,2,3-triazole-4-carboxamido)-1,3,4,5-tetrahydro-2H-benzo[c]azepine-2-carboxylate(556 mg, 3.06 mmol) in CH₂Cl₂ (10 mL) were added HATU (1.16 g, 3.06mmol) and DIPEA (592 mg, 4.6 mmol). The mixture was stirred at rt for 1h before 1-(tert-butyl)-1H-1,2,3-triazole-4-carboxylic acid (1.04 g,3.06 mmol) was added. The mixture was stirred at rt for 12 h. Themixture was diluted with CH₂Cl₂ (200 mL), washed with water (100 mL),brine (100 mL), dried and concentrated. The crude product was purifiedby silica gel column (PE:EtOAc=1:1) to give tert-butyl8-bromo-5-(1-(tert-butyl)-1H-1,2,3-triazole-4-carboxamido)-1,3,4,5-tetrahydro-2H-benzo[c]azepine-2-carboxylate(1.1 g, yield: 73%) as a yellow solid. ESI-MS (M+H)⁺: 492.1. ¹H NMR (400MHz, CDCl₃) δ: 8.17 (s, 1H), 7.35-7.33 (m, 2H), 7.21 (d, J=8.0 Hz, 1H),5.52-5.42 (m, 1H), 4.54-4.34 (m, 2H), 4.04-3.86 (m, 1H), 3.65-3.55 (m,1H), 2.80 (s, 9H), 2.10-2.07 (m, 2H), 1.41 (s, 9H).

2. The Preparation of tert-butyl5-(1-(tert-butyl)-1H-1,2,3-triazole-4-carboxamido)-8-(2-((1-ethyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-1,3,4,5-tetrahydro-2H-benzo[c]azepine-2-carboxylate

Synthesis of tert-butyl5-(1-(tert-butyl)-1H-1,2,3-triazole-4-carboxamido)-8-(2-((1-ethyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-1,3,4,5-tetrahydro-2H-benzo[c]azepine-2-carboxylatewas similar to that of tert-butyl5-(5-(tert-butyl)-1,2,4-oxadiazole-3-carboxamido)-8-(2-((1-ethyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-1,3,4,5-tetrahydro-2H-benzo[c]azepine-2-carboxylatein Example 7. The crude product was purified by silica gel columnchromatography (CH₂Cl₂:MeOH=20:1) to give tert-butyl5-(1-(tert-butyl)-1H-1,2,3-triazole-4-carboxamido)-8-(2-((1-ethyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-1,3,4,5-tetrahydro-2H-benzo[c]azepine-2-carboxylateas a yellow solid (170 mg, Y: 35%). ESI-MS (M+H)⁺: 601.2.

3. The Preparation of1-(tert-butyl)-N-(8-(2-((1-ethyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1H-1,2,3-triazole-4-carboxamide

Synthesis of1-(tert-butyl)-N-(8-(2-((1-ethyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1H-1,2,3-triazole-4-carboxamidewas similar to that of5-(tert-butyl)-N-(8-(2-((1-ethyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1,2,4-oxadiazole-3-carboxamidein Example 7. The crude product (135 mg, yield: 95%) was used in thenext step without further purification. ESI-MS (M+H)⁺: 501.2.

4. The Preparation of1-(tert-butyl)-N-(8-(2-((1-ethyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(oxetan-3-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1H-1,2,3-triazole-4-carboxamide

Synthesis of1-(tert-butyl)-N-(8-(2-((1-ethyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(oxetan-3-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1H-1,2,3-triazole-4-carboxamidewas similar to that of5-(tert-butyl)-N-(8-(2-((1-ethyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(oxetan-3-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1,2,4-oxadiazole-3-carboxamidein Example 7. The crude product was purified by silica gel columnchromatography (EtOAc:MeOH=10:1) to give1-(tert-butyl)-N-(8-(2-((1-ethyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(oxetan-3-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1H-1,2,3-triazole-4-carboxamideas a yellow solid (67 mg, yield: 45%). ESI-MS (M+H)⁺: 556.7. ¹H NMR (400MHz, DMSO-d₆) δ: 9.48 (s, 1H), 9.02 (d, J=8.8 Hz, 1H), 8.76 (s, 1H),8.46 (d, J=5.2 Hz, 1H), 7.97-7.91 (m, 3H), 7.56 (s, 1H), 7.37 (d, J=8.0Hz, 1H), 7.25 (d, J=5.2 Hz, 1H), 5.47-5.43 (m, 1H), 4.61-1.47 (m, 4H),4.13-4.08 (m, 2H), 3.88-3.65 (m, 3H), 2.90-2.78 (m, 2H), 2.15-2.06 (m,1H), 1.88-1.82 (m, 1H), 1.65 (s, 9H), 1.36 (t, J=7.2 Hz, 3H).

Example 24.(R)-1-(tert-butyl)-N-(8-(2-((1-ethyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(oxetan-3-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1H-1,2,3-triazole-4-carboxamide(compound 24a) and(S)-1-(tert-butyl)-N-(8-(2-((1-ethyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(oxetan-3-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1H-1,2,3-triazole-4-carboxamide(compound 24b)

1-(tert-butyl)-N-(8-(2-((1-ethyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(oxetan-3-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1H-1,2,3-triazole-4-carboxamide(50 mg) was subjected to SFC separation (2.1×25.0 cm (S,S) Whelk0-1, 58%methanol with 0.5% isopropylamine/CO₂, 120 bar, 85 mL/min, 230 nm,methanol) and yielded 23 mg of peak-1 (chemical purity 99%, ee>99%) and24 mg of peak-2 (chemical purity 99%, ee=99%).

Peak 1 is assigned as(R)-1-(tert-butyl)-N-(8-(2-((1-ethyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(oxetan-3-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1H-1,2,3-triazole-4-carboxamide:LCMS: Rt 4.0 min, m/z 557.20. ¹H NMR (400 MHz, METHANOL-d₄) δ ppm 8.51(s, 1H), 8.40 (d, J=5.27 Hz, 1H), 8.05-7.92 (m, 3H), 7.64 (s, 1H), 7.47(d, J=8.28 Hz, 1H), 7.21 (d, J=5.27 Hz, 1H), 5.57 (br d, J=9.04 Hz, 1H),4.78-4.71 (m, 1H), 4.71-4.65 (m, 3H), 4.17 (q, J=7.28 Hz, 2H), 4.01-3.91(m, 1H), 3.91-3.78 (m, 2H), 3.15-2.98 (m, 1H), 2.88 (ddd, J=12.99 Hz,9.60 Hz, 3.51 Hz, 1H), 2.36-2.14 (m, 1H), 2.11-1.87 (m, 1H), 1.73 (s,9H), 1.46 (t, J=7.28 Hz, 3H).

Peak 2 is assigned as(S)-1-(tert-butyl)-N-(8-(2-((1-ethyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(oxetan-3-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1H-1,2,3-triazole-4-carboxamide:LCMS: Rt 5.3 min, m/z 557.00. ¹H NMR (400 MHz, METHANOL-d₄) δ ppm 8.51(s, 1H), 8.40 (d, J=5.27 Hz, 1H), 8.06-7.92 (m, 3H), 7.64 (s, 1H), 7.47(d, J=8.03 Hz, 1H), 7.21 (d, J=5.27 Hz, 1H), 5.57 (br d, J=9.29 Hz, 1H),4.77-4.70 (m, 1H), 4.70-4.63 (m, 2H), 4.17 (q, J=7.28 Hz, 2H), 4.05-3.91(m, 1H), 3.91-3.76 (m, 2H), 3.15-2.98 (m, 1H), 2.89 (ddd, J=12.8 Hz, 9.7Hz, 3.6 Hz, 1H), 2.40-2.13 (m, 1H), 2.12-1.87 (m, 1H), 1.74 (s, 9H),1.47 (t, J=7.28 Hz, 3H).

Example 25.(R)-1-(tert-butyl)-N-(8-(2-((1-isopropyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(oxetan-3-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1H-1,2,3-triazole-4-carboxamide(compound 25)

1. Synthesis of tert-butyl(R)-5-(1-(tert-butyl)-1H-1,2,3-triazole-4-carboxamido)-8-(2-((1-isopropyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-1,3,4,5-tetrahydro-2H-benzo[c]azepine-2-carboxylate

Synthesis of tert-butyl(R)-5-(1-(tert-butyl)-1H-1,2,3-triazole-4-carboxamido)-8-(2-((1-isopropyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-1,3,4,5-tetrahydro-2H-benzo[c]azepine-2-carboxylatewas similar to that of tert-butyl(R)-5-(5-(tert-butyl)-1,2,4-oxadiazole-3-carboxamido)-8-(2-((1,5-dimethyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-1,3,4,5-tetrahydro-2H-benzo[c]azepine-2-carboxylate(Example 9, Step 3). The crude material was purified by silica gelchromatography (EtOAc:PE=4:1) to give tert-butyl(R)-5-(1-(tert-butyl)-1H-1,2,3-triazole-4-carboxamido)-8-(2-((1-isopropyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-1,3,4,5-tetrahydro-2H-benzo[c]azepine-2-carboxylateas a yellow solid (520 mg, yield: 56%). ESI-MS (M+H)⁺: 615.3.

2. Synthesis of(R)-1-(tert-butyl)-N-(8-(2-((1-isopropyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1H-1,2,3-triazole-4-carboxamide

Synthesis of(R)-1-(tert-butyl)-N-(8-(2-((1-isopropyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1H-1,2,3-triazole-4-carboxamidewas similar to that of(R)-5-(tert-butyl)-N-(8-(2-((1,5-dimethyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1,2,4-oxadiazole-3-carboxamidein Example 9, Step 4. The crude product was isolated as a yellow solidand was used for the next step without further purification (420 mg,yield: 96%). ESI-MS (M+H)⁺: 515.3.

3. Synthesis of(R)-1-(tert-butyl)-N-(8-(2-((I-isopropyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(oxetan-3-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1H-1,2,3-triazole-4-carboxamide(I-RP35)

Synthesis of(R)-1-(tert-butyl)-N-(8-(2-((1-isopropyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(oxetan-3-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1H-1,2,3-triazole-4-carboxamidewas similar to that of(R)-5-(tert-butyl)-N-(8-(2-((1-isopropyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(oxetan-3-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1,3,4-oxadiazole-2-carboxamidein Example 17. The crude material was purified by silica gelchromatography (DCM:MeOH=20:1) to give(R)-1-(tert-butyl)-N-(8-(2-((1-isopropyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(oxetan-3-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1H-1,2,3-triazole-4-carboxamideas a yellow solid (116 mg, yield: 51%). ESI-MS (M+H)⁺: 571.2. ¹H NMR(400 MHz, CDCl₃) δ: 8.42 (d, J=4.8 Hz, 1H), 8.17 (s, 1H), 8.07 (d, J=8.8Hz, 1H), 7.94 (s, 1H), 7.85 (d, J=8.0 Hz, 1H), 7.77 (s, 1H), 7.57 (s,1H), 7.48 (d, J=8.0 Hz, 1H), 7.11 (s, 1H), 7.03 (d, J=5.2 Hz, 1H), 5.64(t, J=8.0 Hz, 1H), 4.78-4.68 (m, 4H), 4.53-4.45 (m, 1H), 3.91-3.80 (m,3H), 3.04-2.99 (m, 1H), 2.82-2.79 (m, 1H), 2.27-2.23 (m, 1H), 2.10-2.05(m, 1H), 1.70 (s, 9H), 1.55 (s, 3H), 1.52 (s, 3H).

Example 26.1-(tert-butyl)-N—((R)-8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-((R)-tetrahydrofuran-3-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1H-1,2,3-triazole-4-carboxamide(compound 26a) &1-(tert-butyl)-N—((R)-8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-((S)-tetrahydrofuran-3-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1H-1,2,3-triazole-4-carboxamide(compound 26b)

1. Synthesis of tert-butyl(R)-8-bromo-5-(1-(tert-butyl)-1H-1,2,3-triazole-4-carboxamido)-1,3,4,5-tetrahydro-2H-benzo[c]azepine-2-carboxylate

Synthesis of tert-butyl(R)-8-bromo-5-(1-(tert-butyl)-1H-1,2,3-triazole-4-carboxamido)-1,3,4,5-tetrahydro-2H-benzo[c]azepine-2-carboxylatewas similar to that of tert-butyl8-bromo-5-(5-(tert-butyl)-1,3,4-oxadiazole-2-carboxamido)-4,5-dihydro-1H-benzo[c]azepine-2(3H)-carboxylatein Example 12, Step 1. The crude product was purified by silica gelcolumn chromatography (EtOAc/petroleum ether=1:2) to give tert-butyl(R)-8-bromo-5-(1-(tert-butyl)-1H-1,2,3-triazole-4-carboxamido)-1,3,4,5-tetrahydro-2H-benzo[c]azepine-2-carboxylateas yellow solid (2.3 g, yield: 95%). ESI-MS (M+H)⁺: 492.2.

2. Synthesis of tert-butyl(R)-5-(1-(tert-butyl)-1H-1,2,3-triazole-4-carboxamido)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,4,5-tetrahydro-2H-benzo[c]azepine-2-carboxylate

Synthesis of tert-butyl(R)-5-(1-(tert-butyl)-1H-1,2,3-triazole-4-carboxamido)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,4,5-tetrahydro-2H-benzo[c]azepine-2-carboxylatewas similar to the synthesis of tert-butyl(R)-5-(5-(tert-butyl)-1,2,4-oxadiazole-3-carboxamido)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,4,5-tetrahydro-2H-benzo[c]azepine-2-carboxylatedescribed in Example 9, Step 1. The crude product was used for next stepwithout purification. ESI-MS (M+H)⁺: 540.3.

3. Synthesis of tert-butyl(R)-5-(1-(tert-butyl)-1H-1,2,3-triazole-4-carboxamido)-8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-1,3,4,5-tetrahydro-2H-benzo[c]azepine-2-carboxylate

To a solution of tert-butyl(R)-5-(1-(tert-butyl)-1H-1,2,3-triazole-4-carboxamido)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,4,5-tetrahydro-2H-benzo[c]azepine-2-carboxylate(5.4 g, 10.0 mmol) in dioxane/H₂O (100 mL) was added4-chloro-N-(1-methyl-1H-pyrazol-4-yl)pyrimidin-2-amine (2.1 g, 10.0mmol), K₂CO₃ (2.8 g, 20.0 mmol) and Pd(dppf)Cl₂ (0.4 g, 0.5 mmol) wereadded. The mixture was stirred at 100° C. for 16 h under nitrogen. Aftercooling to rt, the mixture was concentrated and purified by silica gelcolumn chromatography (petroleum ether/EtOAc=1:3) to give tert-butyl(R)-5-(1-(tert-butyl)-1H-1,2,3-triazole-4-carboxamido)-8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-1,3,4,5-tetrahydro-2H-benzo[c]azepine-2-carboxylateas a yellow solid (3.2 g, yield: 55%). ESI-MS (M+H)⁺: 586.7. ¹H NMR (400MHz, CDCl₃) δ: 8.42 (s, 1H), 8.19 (s, 1H), 8.02-7.87 (m, 3H), 7.68 (s,1H), 7.54-7.49 (m, 2H), 7.06 (d, J=5.2 Hz, 1H), 5.63-5.58 (m, 1H),4.83-4.67 (m, 1H), 4.51-4.47 (m, 1H), 4.02-4.00 (m, 1H), 3.93 (s, 3H),3.65-3.62 (m, 1H), 2.14-2.12 (m, 2H), 1.72 (s, 9H), 1.41-1.38 (m, 9H).

4. Synthesis of(R)-1-(tert-butyl)-N-(8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1H-1,2,3-triazole-4-carboxamide

To a solution of tert-butyl(R)-5-(1-(tert-butyl)-1H-1,2,3-triazole-4-carboxamido)-8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-1,3,4,5-tetrahydro-2H-benzo[c]azepine-2-carboxylate(3.2 g, 5.5 mmol) in DCM (30 mL) was added TFA (30 mL). The mixture wasstirred at rt for 3 h. The solvent was removed. The crude was dissolvedin MeOH (30 mL)/water (20 mL). The mixture was basified with NH₄OH topH=8-9 and extracted with DCM (3×50 mL). The combined organic layerswere washed with brine, dried over Na₂SO₄, filtered and concentrated togive(R)-1-(tert-butyl)-N-(8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1H-1,2,3-triazole-4-carboxamideas a gray solid (2.6 g, yield: 98%). ESI-MS (M+H)⁺: 486.7.

5. Synthesis of1-(tert-butyl)-N—((R)-8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-((R)-tetrahydrofuran-3-yl)-2,3,4,5-tetrahydro-H-benzo[c]azepin-5-yl)-1H-1,2,3-triazole-4-carboxamide&1-(tert-butyl)-N—((R)-8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-((S)-tetrahydrofuran-3-yl)-2,3,4,5-tetrahydro-H-benzo[c]azepin-5-yl)-1H-1,2,3-triazole-4-carboxamide

To a solution of(R)-1-(tert-butyl)-N-(8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1H-1,2,3-triazole-4-carboxamide(500 mg, 1.0 mmol) in MeOH (30 mL) were added dihydrofuran-3(2H)-one(258 mg, 3.0 mmol), ZnCl₂ (682 mg, 5.0 mmol) and NaBH₃CN (189 mg, 3.0mmol). The mixture was stirred at 50° C. for 16 h. The mixture wasconcentrated and purified by silica gel column chromatography(DCM/MeOH=20/1 to 15/1) to give the racemic product as a yellow solid(542 mg, yield: 79%).

1-(tert-butyl)-N—((R)-8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-((S)-tetrahydrofuran-3-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1H-1,2,3-triazole-4-carboxamide(154 mg) and1-(tert-butyl)-N—((R)-8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-((R)-tetrahydrofuran-3-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1H-1,2,3-triazole-4-carboxamide(167 mg) were separated by chiral resolution. ESI-MS (M+H)⁺: 557.3.

Isomer 1: ¹H NMR (400 MHz, CD₃OD) δ: 8.53 (s, 1H), 8.42 (d, J=5.2 Hz,1H), 8.05-7.99 (m, 3H), 7.64 (s, 1H), 7.48 (d, J=8.4 Hz, 1H), 7.23 (d,J=5.2 Hz, 1H), 5.58 (d, J=10.4 Hz, 1H), 4.16-4.09 (m, 2H), 4.02-3.96 (m,2H), 3.90 (s, 3H), 3.79-3.71 (m, 2H), 3.31-3.24 (m, 2H), 3.15-3.10 (m,1H), 2.31-2.17 (m, 2H), 2.07-1.97 (m, 2H), 1.74 (s, 9H).

Isomer 2: ¹H NMR (400 MHz, CD₃OD) δ: 8.43 (s, 1H), 8.30 (d, J=5.2 Hz,1H), 7.95-7.86 (m, 3H), 7.67 (s, 1H), 7.37 (d, J=8.0 Hz, 1H), 7.13 (d,J=5.2 Hz, 1H), 5.47 (d, J=9.6 Hz, 1H), 4.00 (br, 2H), 3.93-3.85 (m, 2H),3.85 (s, 3H), 3.69-3.58 (m, 2H), 3.28-3.22 (m, 1H), 3.17-2.97 (m, 2H),2.21-2.01 (m, 2H), 1.99-1.80 (m, 2H), 1.63 (s, 9H).

Example 27a.(R)-1-(tert-butyl)-N-(8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(oxetan-3-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1H-1,2,3-triazole-4-carboxamide(compound 27)

To a solution of(R)-1-(tert-butyl)-N-(8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1H-1,2,3-triazole-4-carboxamide(500 mg, 1.0 mmol) in MeOH (30 mL) were added oxetan-3-one (216 mg, 3.0mmol), ZnCl₂(682 mg, 5.0 mmol) and NaBH₃CN (189 mg, 3.0 mmol). Themixture was stirred at 50° C. for 3 h. The mixture was concentrated andthe crude material was purified by silica gel chromatography(CH₂Cl₂:MeOH grading from 20:1 to 15:1) to give(R)-1-(tert-butyl)-N-(8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(oxetan-3-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1H-1,2,3-triazole-4-carboxamideas a yellow solid (307 mg, yield: 55%). ESI-MS (M+H)⁺: 542.7. ¹H NMR(400 MHz, CD₃OD) δ: 8.54 (s, 1H), 8.42 (d, J=5.6 Hz, 1H), 8.04-7.98 (m,3H), 7.71 (s, 1H), 7.49 (d, J=8.0 Hz, 1H), 7.24 (d, J=5.2 Hz, 1H), 5.59(d, J=9.2 Hz, 1H), 4.79-4.75 (m, 1H), 4.71-4.69 (m, 3H), 4.00-3.83 (m,6H), 3.09-3.05 (m, 1H), 3.94-2.88 (m, 1H), 2.29-2.21 (m, 1H), 2.07-2.04(m, 1H), 1.75 (s, 9H).

Example 27b.(R)-1-(tert-butyl)-N-(8-(2-((1-(methyl-d3)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(oxetan-3-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1H-1,2,3-triazole-4-carboxamide 1.Synthesis of 1-(methyl-d3)-1H-pyrazol-4-amine

A mixture of 4-nitro-1-pyrazole (5.0 g, 44 mmol) and d6-dimethyl sulfate(10.0 g, 75.7 mmol) in 1 M solution of NaOH in water (50.0 mL) washeated at 35° C. overnight. The solid formed was filtered, washed withwater, and dried (Na₂SO₄) to give 1-d3-methyl-4-nitro-1-pyrazole as awhite crystal (3.9 g, yield: 68%). LCMS: RT 0.36 min.; MH+131.1; 1H NMR(400 MHz, DMSO-d6) δ: 8.84 (s, 1H), 8.23 (s, 1H).

2. Synthesis of 1-(methyl-d3)-4-nitro-1H-pyrazole

A solution of 1-d3-methyl-4-nitro-1-pyrazole (3.9 g, 30 mmol) in EtOH(50.0 mL) was degassed with nitrogen, followed by the addition of 10%palladium on carbon (0.32 g, 0.30 mmol).

The mixture was placed under an atmosphere of hydrogen and stirred at rtfor 2 h. The mixture was filtered and the filtrate was concentrated invacuo to give 1-(d3-methyl-1H-pyrazol-4-amine as an oil (2.9 g, yield:96%) which was used in the next step without further purification.

3. Synthesis of4-methoxy-N-(1-(methyl-d3)-1H-pyrazol-4-yl)pyrimidin-2-amine

To a solution of 2-chloro-4-methoxypyrimidine (9.4 g, 65.1 mmol) in1,4-dioxane (0.3 L) was added 1-methyl-d3-1H-pyazol-4-amine (8.5 g, 85mmol), Cs₂CO₃ (63.6 g, 195 mmol), S-Phos (13.3 g, 0.03 mol) andPd₂(dba)₃ (16.7 g, 0.02 mol). The reaction mixture was stirred at refluxunder N₂ for 16 h. The reaction mixture was cooled to room temperatureand the mixture was filtered through a silica gel pad, and washed withEtOAc (500 mL). The combined filtrates were concentrated in vacuo. Thecrude material was purified by silica gel chromatography(heptane:EtOAc=100:0 to 0:100) to give4-methoxy-N-(1-(methyl-d3)-1H-pyrazol-4-yl)pyrimidin-2-amine (9.2 g,yield: 68%) as a light yellow solid. ESI-MS (M+H)⁺: 209.1. ¹H NMR (400MHz, CDCl₃) δ: 8.10 (d, J=5.7 Hz, 1H), 7.77 (s, 1H), 7.51 (s, 1H), 6.13(d, J=5.7 Hz, 1H), 3.94 (s, 3H).

4. Synthesis of4-chloro-N-(1-(methyl-d3)-1H-pyrazol-4-yl)pyrimidin-2-amine

To 4-methoxy-N-(1-(methyl-d3)-1H-pyrazol-4-yl)pyrimidin-2-amine (9.1 g,43.7 mmol) was added HBr (90 mL, 38% aqueous). The reaction mixture washeated to 100° C. and stirred at that temperature for 3 h. The reactionmixture was cooled to room temperature and concentrated in vacuo,azetroped with toluene (3×100 mL) and dried at 50° C. overnight toafford the HBr salt (16 g) as a yellow/brown solid. The salt was thendissolved in POCl₃ (250 mL) and heated to 100° C. for 36 hrs. Thereaction mixture was cooled to room temperature and concentrated invacuo and azetroped with Toluene (3×100 mL). the resulting residue wasdiluted with EtOAc (500 mL) and water (100 mL) and the layer wereseparated. The aqueous layer was extracted with EtOAc (3×100 mL) and thecombined organic layers were washed with brine (200 mL), dried (Na₂SO₄),filtered and concentrated in vacuo to afford a residue which wastriturated with EtOAc/heptanes (1:1) to afford added to4-chloro-N-(1-(methyl-d3)-1H-pyrazol-4-yl)pyrimidin-2-amine as a whitesolid (7.4 g, yield: 80%). ESI-MS (M+H)⁺: 213.0.

5. Synthesis of tert-butyl(R)-5-(1-(tert-butyl)-1H-1,2,3-triazole-4-carboxamido)-8-(2-((1-(methyl-d3)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-1,3,4,5-tetrahydro-2H-benzo[c]azepine-2-carboxylate

To a solution of tert-butyl(R)-5-(1-(tert-butyl)-1H-1,2,3-triazole-4-carboxamido)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,4,5-tetrahydro-2H-benzo[c]azepine-2-carboxylate(4.6 g, 8.5 mmol) in 1,4-dioxane (100 mL) and water (20 mL) was added4-chloro-N-(1-(methyl-d3)-1H-pyrazol-4-yl)pyrimidin-2-amine (1.8 g, 8.5mmol), K₂CO₃ (2.4 g, 17 mmol) and Pd(dppf)Cl₂ (0.7 g, 0.85 mmol) wereadded. The mixture was stirred at 100° C. for 16 h under nitrogen. Aftercooling to rt, the mixture was diluted with EtOAc (300 mL) and washedwith saturated brine (100 mL). The aqueous layer was extracted withEtOAc (3×100 mL) and the organics were combined, dried (Na₂SO₄),filtered, concentrated in vacuo to afford a residue. The crude materialwas purified by silica gel column chromatography (gradientheptanes/EtOAc=100:0-0:100) to give tert-butyl(R)-5-(1-(tert-butyl)-1H-1,2,3-triazole-4-carboxamido)-8-(2-((1-(methyl-d3)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-1,3,4,5-tetrahydro-2H-benzo[c]azepine-2-carboxylateas a yellow solid (3.2 g, yield: 55%). ESI-MS (M+H)⁺: 590.4.

6. Synthesis of(R)-1-(tert-butyl)-N-(8-(2-((1-(methyl-d3)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1H-1,2,3-triazole-4-carboxamide

To a solution of tert-butyl(R)-5-(1-(tert-butyl)-1H-1,2,3-triazole-4-carboxamido)-8-(2-((1-(methyl-d3)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-1,3,4,5-tetrahydro-2H-benzo[c]azepine-2-carboxylate(3.2 g, 5.5 mmol) in CH₂Cl₂ (40 mL) was added TFA (40 mL). The mixturewas stirred at rt for 3 h. The solvent was removed and the crudematerial was re-dissolved in MeOH (30 mL)/water (20 mL). The mixture wasbasified with NH₄OH to pH=8-9 and extracted with CH₂Cl₂ (3×100 mL). Thecombined organic layers were washed with brine (100 mL), dried overNa₂SO₄, filtered and concentrated in vacuo to give(R)-1-(tert-butyl)-N-(8-(2-((1-(methyl-d3)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1H-1,2,3-triazole-4-carboxamideas a yellow solid (3.0 g, yield: 86%). ESI-MS (M+H)⁺: 490.2.

7.(R)-1-(tert-butyl)-N-(8-(2-((1-(methyl-d3)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(oxetan-3-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1H-1,2,3-triazole-4-carboxamide

(R)-1-(tert-butyl)-N-(8-(2-((1-methyl-d3)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1H-1,2,3-triazole-4-carboxamide(2.6 g, 15.9 mmol) was dissolved in MeOH (160 mL) and treated withoxetan-3-one (1.15 g, 16.0 mmol), ZnCl₂ (3.6 g, 26.5 mmol) and NaBH₃CN(1.0 mg, 15.9 mmol). The mixture was stirred at 50° C. for 16 h,concentrated in vacuo and the crude material was purified by silica gelchromatography (gradient CH₂Cl₂:MeOH 100:10) to give a yellow solidwhich was further washed purified by dissolving in MeOH (100 mL) andCH₂Cl₂ (500 mL) and washed with water (100 mL) and saturated brine (100mL), the organic layer was separated, dried (Na₂SO₄), filtered andconcentrated in vacuo to afford(R)-1-(tert-butyl)-N-(8-(2-((1-methyl-d3)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(oxetan-3-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1H-1,2,3-triazole-4-carboxamideas a yellow solid (2.32 g, 67% yield: 55%). ESI-MS (M+H)⁺: 546.3.

¹H NMR (400 MHz, DMSO-d₆) δ: 9.46 (s, 1H), 8.98 (d, J=8.3 Hz, 1H), 8.74(s, 1H), 8.46 (d, J=5.6 Hz, 1H), 7.95 (m, 3H), 7.54 (s, 1H), 7.38 (d,J=8.1 Hz, 1H), 7.25 (d, J=5.2 Hz, 1H), 5.45 (m, 1H), 4.61-4.47 (m, 4H),3.86 (m, 1H), 3.78 (m, 1H), 3.67 (m, 1H), 2.93 (m, 1H), 2.77 (m, 1H),2.12 (m, 1H), 1.86 (m, 1H), 1.66 (s, 9H).

Example 27c. Preparation of Crystalline Form A and Crystalline Form G ofCompound 27

Compound(R)-1-(tert-butyl)-N-(8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1H-1,2,3-triazole-4-carboxamide(1200 g, 2.47 mol) was added to a 20 L reactor at room temperature (25°C.), followed by addition of 24 L of 1,2-dichloroethane at 25° C. To thesolution was added oxetan-3-one (534 g, 24.7 mol), NaBH(OAc)₃ (523 g,2.47 mol), and AcOH (24 mL, 0.17 eq). An additional amount of NaBH(OAc)₃(1046 g, 4.94 mol) was added in portion to the reactor at roomtemperature. The mixture was stirred at 25° C. for 16 h. Ice water (12kg) was added slowly to reactor at room temperature. The organic layerwas separated and the aqueous layer was extracted with dichloromethanethree time (3×12 L). The combined organic layer was washed with brine(20 L), dried over Na₂SO₄, filtered and concentrated. The crude materialwas purified by silica gel chromatography (CH₂Cl₂:MeOH=20:1) to afford(R)-1-(tert-butyl)-N-(8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(oxetan-3-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1H-1,2,3-triazole-4-carboxamide(compound 27).

The purified compound 27 (950 g) and EtOH (5 L) were vigorously stirredfor 4 h and the slurry was filtered and washed with 1 L EtOH. Theresulting wet cake was dried under vacuum at 45° C. for ˜24 h untilreaching a constant weight to afford crystalline Form A (960 g, yield85.7%, purity 99%).

300.2 mg of crystalline Form A was weighed into a 20 mL glass vialfollowed by addition of 6 mL of isopropyl acetate (IPAc) for suspension.The sample was magnetically stirred at 50° C. with a rate of ˜1000 rpmfor three days. Solids were isolated by filtration after three days andthen dried at room temperature under vacuum for about 5 h to yieldcrystalline Form G.

Alternatively, to 2.1 g of crystallinze Form A was charged 15 volumes ofdichloromethane (mL/g). Distill the resulting mixture under atmosphericconditions using a Dean-Stark trap under the conditions ofT_(j)−T_(r)=20 K and T_(jmax)=110° C., wherein T_(j)=jacket temperature,T_(r)=reaction/reactor temperature and T_(jmax)=max jacket temperature.5 mL or 2 volumes of dichloromethane was removed, followed by additionof 2 volumes of isopropyl acetate (IPAc). Continue to distill under theconditions of T_(j)−T_(r)=40K and T_(jmax)=110° C. until 10 mL or 5volumes of the solvent(s) was removed. 5 volumes of IPAc was then added,followed by continued distillation to remove another 10 mL or 5 volumesof the solvent(s). 5 volumes of IPAc was added followed by an additional30 mL of IPAc. The resulting mixture was stirred and temperature wascycled over the weekend between 20° C. to 60° C. to form a slurry andForm G was isolated from the slurry.

Powder X-Ray Diffraction

Crystallinity of the compound was studied using a XRD-D8 X-ray powderdiffractometer using Cu Ka radiation (Bruker, Madison, Wis.). Theinstrument is equipped with a long fine focus X-ray tube. The tubevoltage and amperage were set to 40 kV and 40 mA, respectively. Thedivergence and scattering slits were set at 10 and the receiving slitwas set at 0.15 mm. Diffracted radiation was detected by a Lynxeyedetector. A θ-2θ continuous scan at 1.6°/min from 3 to 42° 2θ was used.The sample was prepared for analysis by placing it on a zero backgroundplate.

The powder X-ray diffraction (PXRD) pattern of crystalline Form A isshown in FIG. 1 and the main peaks are listed in Table 1. The PXRDpattern of crystalline Form G is shown in FIG. 4 and the main peaks arelisted in Table 2.

TABLE 1 PXRD peak list for crystalline Form A 2θ angle Net IntensityRelative Intensity 4.31 53.6 0.08 5.68 700.9 1.00 7.94 247.9 0.35 8.73136.1 0.19 9.65 176.0 0.25 11.89 168.3 0.24 13.05 91.4 0.13 14.79 118.90.17 15.17 61.7 0.09 16.08 171.5 0.24 4.31 53.6 0.08 5.68 700.9 1.007.94 247.9 0.35 8.73 136.1 0.19 9.65 176.0 0.25 16.96 164.8 0.24 17.82132.6 0.19 18.21 488.1 0.70 19.02 208.4 0.30 20.45 143.8 0.21 21.23116.4 0.17 16.96 164.8 0.24 22.42 248.8 0.35 22.80 79.2 0.11 23.79 136.40.19 25.61 103.5 0.15

TABLE 2 PXRD peak list for crystalline Form G 2θ angle Net IntensityRelative Intensity 3.62 1071.5 0.58 8.92 96.8 0.05 10.96 184.5 0.1012.59 206.5 0.11 14.53 81.6 0.04 15.41 252.1 0.14 16.33 133.3 0.07 18.44294.9 0.16 20.18 701.1 0.38 21.79 1860.2 1.00 23.36 205.8 0.11 25.40502.9 0.27 26.78 34.5 0.02 34.18 28.8 0.02Differential Scanning Calorimetry (DSC) and Thermogravimetric Analysis(TGA)

Thermal properties of the compound were examined using a DiscoveryDifferential Scanning Calorimeter (DSC) (TA Instruments) and a DiscoveryThermogravimetric Analyzer (TGA) (TA Instruments). Sample was enclosedin a closed aluminum DSC pan for DSC analysis and in an open aluminumpan for TGA analysis. The thermal analysis was performed with a lineargradient from 25° C. to 300° C. at 10° C. per minute for both DSC andTGA studies. The differential scanning calorimetry (DSC) analysis forcrystalline Form A shows that Form A has an onset temperature at 175.6°C. and a melting temperature at 186° C. (FIG. 2).

The DSC analysis for crystalline Form G shows that Form G has an onsettemperature at 215.4° C. and a melting temperature at 217.3° C. (FIG.5).

The TGA analysis for Form A of compound 27 shows a 3.16% weight loss,indicating Form A is a hydrate (FIG. 3).

The TGA analysis of Form G of compound 27 shows no weight loss until themelt, indicating that Form G is anhydrous (FIG. 5).

Solid State NMR

The ¹³C CP/MAS (Cross polarization/magic angle spinning) solid-state NMRspectra were acquired on a 363 MHz Tecmag Redstone spectrometer bySpectral Data Services of Champaign, Ill. Each sample was packed into a7 mm (OD) zirconia rotor closed with kel-F end caps for subsequent dataacquisition. All three samples were about half full in the rotor. The¹³C CP/MAS NMR spectra were acquired on the Doty XC 7 mm CP/MAS probe atan observing frequency of 91 MHz (spin 7 kHz, 1H pulse width 5.0 μs,spectral width 29.8 kHz, acquisition time 0.0344 sec, CP pulse width 2ms, relaxation delay 5.0 sec, number of scans 1296). Spectra werereferenced to the chemical shift of external sample of glycine carbonylcarbon at 176 ppm and processed using Nuts (line broadening of 10 Hz).The peak listing and overlay of spectra are processed using MNOVA.

¹³C CP/MAS solid state NMR for Form A and Form G are shown in FIG. 3Band FIG. 6B, respectively. Diagnostic chemical shifts are listed inTable 3.

TABLE 3 Diagnostic ¹³C CP/MAS NMR chemical shifts for solid forms ofcompound 27 Peak assignment* Form A (ppm) Form G (ppm) carbonyl 163.2163.6 163.2 aromatic carbons 159.5 157.9 159.4 156.2 (shoulder) 147.0143.7 146.0 142.5 (shoulder) 141.5 135.8 140.6 134.4 137.1 132.3 136.0130.5 130.2 129.6 125.9 126.9 125.0 124.7 120.7 123.6 105.9 106.1 104.4105.1 aliphatic carbons 77.4 77.7 75.9 76.8 60.7 75.5 59.5 61.4 55.960.9 51.6 58.2 50.3 54.4 39.5 51.7 37.9 49.9 35.2 40.0 30.1 37.3 29.130.0 *This is a tentative assignment based on the chemical structure andChemDraw chemical shift prediction and solution ¹³C NMR spectra in DMSO

Example 28.(R)-1-(tert-butyl)-N-(8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(2,2,2-trifluoroethyl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1H-1,2,3-triazole-4-carboxamide(compound 28)

To a solution of(R)-1-(tert-butyl)-N-(8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1H-1,2,3-triazole-4-carboxamide(200 mg, 0.4 mmol) in CH₃CN (5 mL) was added 2,2,2-trifluoroethyltrifluoromethanesulfonate (190 mg, 0.6 mmol). The mixture was stirred at50° C. for 12 h. After concentration of the reaction mixture, theresidue was purified by silica gel chromatography (PE:EtOAc=1:1) to give(R)-1-(tert-butyl)-N-(8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(2,2,2-trifluoroethyl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1H-1,2,3-triazole-4-carboxamideas a yellow solid (85 mg, yield: 36%). ESI-MS (M+H)⁺: 569.3. ¹H NMR (400MHz, CD₃OD) δ: 8.54 (s, 1H), 8.42 (d, J=5.2 Hz, 1H), 8.03-7.99 (m, 3H),7.61 (s, 1H), 7.49 (d, J=7.6 Hz, 1H), 7.22 (d, J=5.2 Hz, 1H), 5.60-5.57(m, 1H), 4.39-4.35 (m, 1H), 4.17-4.12 (m, 1H), 3.89 (s, 3H) 3.43-3.32(m, 2H), 3.16-3.09 (m, 2H), 2.24-2.20 (m, 1H), 1.98-1.94 (m, 1H), 1.74(s, 9H).

Example 29.1-(tert-butyl)-N—((R)-2-((R)-2-hydroxypropyl)-8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1H-1,2,3-triazole-4-carboxamide(compound 29)

To a solution of(R)-1-(tert-butyl)-N-(8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1H-1,2,3-triazole-4-carboxamide(250 mg, 0.51 mmol) in EtOH (5 mL) were added (R)-2-methyloxirane (58mg, 1.0 mmol). The mixture was stirred at 50° C. for 24 h. Afterconcentration, the residue purified by silica gel column (petroleumether/EtOAc=1:2) to give1-(tert-butyl)-N—((R)-2-((R)-2-hydroxypropyl)-8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1H-1,2,3-triazole-4-carboxamideas a white solid (110 mg, yield: 40%). ESI-MS (M+H)⁺: 545.3. ¹H NMR (400MHz, CD₃OD) δ: 8.42 (s, 1H), 8.28 (d, J=5.2 Hz, 1H), 7.93-7.84 (m, 3H),7.52 (s, 1H), 7.35 (d, J=8.8 Hz, 1H), 7.09 (d, J=5.2 Hz, 1H), 5.46 (d,J=10 Hz, 1H), 4.13-4.00 (m, 2H), 3.92-3.87 (m, 1H), 3.78 (s, 3H)3.21-3.12 (m, 2H), 2.40-2.32 (m, 2H), 2.17-2.13 (m, 1H), 1.89-1.84 (m,1H), 1.62 (s, 9H), 1.02 (d, J=6.0 Hz, 3H).

Example 30.1-(tert-butyl)-N—((R)-2-((S)-2-hydroxypropyl)-8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1H-1,2,3-triazole-4-carboxamide(compound 30)

Synthesis of1-(tert-butyl)-N—((R)-2-((S)-2-hydroxypropyl)-8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1H-1,2,3-triazole-4-carboxamidewas similar to that of1-(tert-butyl)-N—((R)-2-((R)-2-hydroxypropyl)-8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1H-1,2,3-triazole-4-carboxamide(Example 29). The crude was purified by prep-TLC (DCM/MeOH=10:1) to give1-(tert-butyl)-N—((R)-2-((S)-2-hydroxypropyl)-8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1H-1,2,3-triazole-4-carboxamideas a yellow solid (97 mg, yield: 44%). ESI-MS (M+H)⁺: 545.3. ¹H NMR (400MHz, CD₃OD) δ: 8.54 (s, 1H), 8.41 (d, J=5.2 Hz, 1H), 8.01-7.97 (m, 3H),7.63 (s, 1H), 7.46 (d, J=8.0 Hz, 1H), 7.22 (d, J=5.6 Hz, 1H), 5.57 (d,J=9.6 Hz, 1H), 4.23-4.20 (m, 1H), 4.12-4.07 (m, 1H), 4.02-3.97 (m, 1H),3.90 (s, 3H), 3.30-3.28 (m, 1H), 3.26-3.19 (m, 1H), 2.47-2.45 (m, 2H),2.31-2.22 (m, 1H), 2.01-1.97 (m, 1H), 1.74 (s, 9H), 1.16 (d, J=6.4 Hz,3H).

Example 31.(R)-1-(tert-butyl)-N-(2-(2-methoxyethyl)-8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1H-1,2,3-triazole-4-carboxamide(compound 31)

To a solution of(R)-1-(tert-butyl)-N-(8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1H-1,2,3-triazole-4-carboxamide(140 mg, 0.29 mmol) in MeOH (10 mL) were added 1-bromo-2-methoxyethane(121 mg, 0.87 mmol) and K₂CO₃ (120 mg, 0.87 mmol). The mixture wasstirred at 80° C. for 16 h. After diluting with water (20 mL), themixture was extracted with CH₂Cl₂ (30 mL×2). The combined organic layerswere washed with H₂O (20 mL×2), dried (Na₂SO₄), filtered andconcentrated. The crude material was purified by prep-TLC(DCM:MeOH=20:1) to give(R)-1-(tert-butyl)-N-(2-(2-methoxyethyl)-8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1H-1,2,3-triazole-4-carboxamideas a yellow solid (66 mg, yield: 42%). ESI-MS (M+H)⁺: 545.1. ¹H NMR (400MHz, CDCl₃) δ: 8.41 (d, J=5.2 Hz, 1H), 8.18 (s, 1H), 7.98 (d, J=8.4 Hz,1H), 7.90 (s, 1H), 7.84 (d, J=8.0 Hz, 1H), 7.80 (s, 1H), 7.53 (s, 1H),7.46 (d, J=8.0 Hz, 1H), 7.04 (d, J=5.2 Hz, 1H), 6.97 (s, 1H), 5.60 (t,J=8.8 Hz, 1H), 4.19-4.07 (m, 2H), 3.91 (s, 3H), 3.57 (t, J=5.6 Hz, 2H),3.37 (s, 3H), 3.32-3.26 (m, 1H), 3.19-3.15 (m, 1H), 2.78-2.69 (m, 2H),2.24-2.20 (m, 1H), 2.02-1.99 (m, 1H), 1.70 (s, 9H).

Example 32.(R)-5-(tert-butyl)-N-(2-(2,2-difluoroethyl)-8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1,3,4-oxadiazole-2-carboxamide(compound 32)

To a solution of(R)-5-(tert-butyl)-N-(8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1,3,4-oxadiazole-2-carboxamide(105 mg, 0.21 mmol) in CH₃CN (8 mL) was added 1,1-difluoro-2-iodoethane(23 μL, 0.26 mmol) and potassium carbonate (89 mg, 0.64 mmol). Themixture was stirred at 80° C. for 18 h. The reaction mixture was cooledto room temperature and filtered. The filtrate was concentrated and thecrude product was purified by prep-HPLC (CH₃CN/H₂O with 0.05% TFA asmobile phase) to give(R)-5-(tert-butyl)-N-(2-(2,2-difluoroethyl)-8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1,3,4-oxadiazole-2-carboxamideas a yellow solid (30 mg, yield: 25%). ESI-MS (M+H)⁺: 552.0. ¹H NMR (400MHz, METHANOL-d₄) δ: 8.42 (d, J=5.3 Hz, 1H), 8.23 (d, J=8.4 Hz, 1H),8.19 (s, 1H), 7.95 (s, 1H), 7.68-7.65 (m, 1H), 7.62 (d, J=7.8 Hz, 1H),7.30 (d, J=5.5 Hz, 1H), 6.40 (tt, J=53.5 Hz, 3.6 Hz, 1H), 5.70 (dd,J=9.8 Hz, 2.5 Hz, 1H), 4.83 (br d, J=14.3 Hz, 1H), 4.67 (br d, J=14.3Hz, 1H), 3.90 (s, 3H), 3.83-3.67 (m, 2H), 3.59 (dt, J=15.0 Hz, 3.4 Hz,2H), 2.52-2.31 (m, 2H), 1.49 (s, 9H)

Example 33.5-(tert-butyl)-N-(2-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl)-1,2,4-oxadiazole-3-carboxamide(compound 33)

1. Synthesis of (E)-5-(3-bromophenyl)pent-4-enoic acid

To a solution of (3-carboxypropyl)triphenylphosphonium bromide (12.87 g,30 mmol, 1.0 equiv) in dry DMSO (50 mL) was added NaH (3 g, 75 mmol, 2.5equiv) by portions at 0° C. The reaction was stirred at room temperaturefor 30 min before 3-bromobenzaldehyde (5.5 g, 30 mmol, 1.0 equiv) wasdropwise added. The mixture was stirred at room temperature for another2 h and then poured into water (200 mL) and extracted with EtOAc (100mL). The aqueous solution was acidified with concentrated HCl andextracted with EtOAc (200 mL×3). The combined organic layer was washedwith brine (100 mL×3). The organic layer was dried over sodium sulfateand concentrated under reduced pressure. The residue was purified bysilica gel column (petroleum ether/EtOAc=2:1) to give(E)-5-(3-bromophenyl)pent-4-enoic acid (4.4 g, yield: 58%) as a yellowoil. ESI-MS (M+1)⁺: 254.9. ¹H NMR (400 MHz, CDCl₃) δ: 7.48 (s, 1H), 7.33(d, J=7.6 Hz, 1H), 7.23 (d, J=8.0 Hz, 1H), 7.15 (t, J=8.0 Hz, 1H),6.39-6.35 (m, 1H), 6.23-6.19 (m, 1H), 2.55-2.53 (m, 4H).

2. Synthesis of 5-(3-bromophenyl)pentanoic acid

To a solution of (E)-5-(3-bromophenyl)pent-4-enoic acid (2.4 g, 9.4mmol, 1.0 equiv) in ethanol (20 mL) was added PtO₂ (200 mg, 10%). Themixture was stirred for 1 h under hydrogen atmosphere. The catalyst wasfiltered out and the resulting filtrate was concentrated to give targetcompound 5-(3-bromophenyl)pentanoic acid (2.1 g, yield: 87%) as a yellowsolid, which was used to next step without further purification. ESI-MS(M+1)⁺: 256.9. ¹H NMR (400 MHz, CD₃OD) δ: 7.24 (s, 1H), 7.21-7.18 (m,1H), 7.06-7.03 (m, 2H), 2.50 (t, J=6.8 Hz, 2H), 2.20 (t, J=6.8 Hz, 2H),1.53-1.51 (m, 4H).

3. Synthesis of 2-bromo-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-one

A mixture of 5-(3-bromophenyl)pentanoic acid (2.1 g, 8.2 mmol, 1.0equiv) in PPA (5 ml) was stirred at 130° C. for 1 h. After cooling down,the mixture was basified to pH=7˜8 with NaOH (1 N). The mixture wasextracted with EtOAc (200 mL×2). The combined organic layers wasconcentrated and purified by prep-HPLC (Gradient: 5% B increase to 95%B, A: 0.5% NH₃ in water, B: CH₃CN) to give2-bromo-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-one (1.1 g, yield: 56%)as a colorless oil. ESI-MS (M+H)⁺: 239.0. ¹H NMR (400 MHz, CDCl₃) δ:7.59 (d, J=8.4 Hz, 1H), 7.43 (dd, J=8.4, 2.0 Hz, 1H), 7.38 (s, 1H), 2.89(t, J=6.8 Hz, 2H), 2.72 (t, J=6.0 Hz, 2H), 1.90-1.79 (m, 4H).

4. Synthesis of 2-bromo-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-ol

To a solution of 2-bromo-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-one(600 mg, 2.5 mmol, 1.0 equiv) in MeOH (10 mL) was added NaBH₄ (144 mg,3.8 mmol, 1.5 equiv) and then stirred at room temperature for 1 h. Afterevaporation of the solvent, the residue was purified by silica gelcolumn (EtOAc/hexane=1:5) to give2-bromo-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-ol (600 mg, yield: 99%)as a white solid. ESI-MS (M+H-17)⁺: 222.9. ¹H NMR (400 MHz, CDCl₃) δ:7.34-7.30 (m, 2H), 7.24 (s, 1H), 4.88-4.86 (m, 1H), 2.88-8.82 (m, 1H),2.70-2.63 (m, 1H), 2.08-2.00 (m, 2H), 1.81-1.72 (m, 4H).

5. Synthesis of 5-azido-2-bromo-6,7,8,9-tetrahydro-5H-benzo[7]annulene

A solution of 2-bromo-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-ol (600mg, 2.5 mmol, 1.0 equiv) in toluene (10 mL) was cooled in an ice bathunder N₂ and treated with DPPA (2.06 g, 7.5 mmol, 3.0 equiv) in oneportion followed by DBU (1.14 g, 7.5 mmol, 3.0 equiv). The reactiontemperature was kept at 0° C. for 1 h and then was warmed to roomtemperature for 12 h. The mixture was diluted with EtOAc (100 mL),washed with 2N HCl (2×50 mL), brine and the organic layer was dried overNa₂SO₄, filtered then concentrated. The crude product was purified bysilica gel column (eluted with PE) to give5-azido-2-bromo-6,7,8,9-tetrahydro-5H-benzo[7]annulene (350 mg, yield:45%) as a yellow oil. ESI-MS (M+H-N₃)⁺: 223.0. ¹H NMR (400 MHz, CDCl₃)δ: 7.31-7.29 (m, 2H), 7.15 (d, J=8.0 Hz, 1H), 4.72 (t, J=5.2 Hz, 1H),2.99-2.92 (m, 1H), 2.70-2.64 (m, 1H), 2.08-2.00 (m, 1H), 1.90-1.59 (m,5H).

6. Synthesis of 2-bromo-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-amine

To a mixture of 5-azido-2-bromo-6,7,8,9-tetrahydro-5H-benzo[7]annulene(375 mg, 1.4 mmol, 1.0 equiv) in THF (5 mL) and H₂O (0.5 mL) was addedPPh₃ (741 mg, 2.8 mmol, 2.0 equiv). The mixture was stirred at roomtemperature for 12 h. The mixture was acidified to pH=1 with HCl (1 N)and extracted with EtOAc (100 mL). The separated aqueous layer wasbasified to pH=10 with NaOH (1 N). The resulting precipitate wascollected and dried to give2-bromo-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-amine (360 mg, yield:100%) as a white solid. ESI-MS (M+H-17)⁺: 222.9.

7. Synthesis of tert-butyl(2-bromo-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl)carbamate

To a mixture of tert-butyl(2-bromo-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl)carbamate (360 mg,1.5 mmol, 1.0 equiv) in CH₂Cl₂ (5 mL) and triethylamine (303 mg, 3.0mmol, 2.0 equiv) was added Boc₂O (394 mg, 1.8 mmol, 1.2 equiv). Themixture was stirred at room temperature for 2 h. After diluted withEtOAc (100 mL), the mixture was washed with water (100 mL×2). Theorganic layer was concentrated and purified by silica gel column(PE:EtOAc=30:1) to give tert-butyl(2-bromo-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl)carbamate (310 mg,yield: 61%) as a white solid. ESI-MS (M-55): 284.0. ¹H NMR (400 MHz,CDCl₃) δ: 7.29-7.23 (m, 2H), 7.10 (d, J=8.0 Hz, 1H), 4.92-4.82 (m, 2H),2.84-2.75 (m, 2H), 1.88-1.83 (m, 5H), 1.44 (s, 9H).

8. Synthesis of tert-butyl(2-(2-chloropyrimidin-4-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl)carbamate

Synthesis of tert-butyl(2-(2-chloropyrimidin-4-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl)carbamatewas similar to that of tert-butyl 4-(2-chloropyrimidin-4-yl)-2-methylcarbamate. The mixture was concentrated and purified by silica gelcolumn (PE:EtOAc=4:1) to give tert-butyl(2-(2-chloropyrimidin-4-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl)carbamate(200 mg, yield: 66%) as a white solid. ESI-MS (M+H)⁺: 374.1.

9. Synthesis of tert-butyl(2-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl)carbamate

A mixture of tert-butyl(2-(2-chloropyrimidin-4-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl)carbamate(500 mg, 1.34 mmol), 1-methyl-1H-pyrazol-4-amine (195 mg, 2.01 mmol),Pd₂(dba)₃ (120 mg, 0.13 mmol), S-phos (111 mg, 0.27 mmol) and Cs₂CO₃(870 mg, 2.68 mmol) in 1,4-dioxane (12 ml) was stirred at 100° C. for 6h under N₂. The mixture was filtrated through a Celite pad and thefiltrate was concentrated. The residue was purified by silica-gel-column(EtOAc) to give tert-butyl(2-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl)carbamateas a white solid (480 mg, yield: 83%). ESI-MS (M+H)⁺: 435.3. ¹H NMR (400MHz, CDCl₃) δ: 8.46 (d, J=5.2 Hz, 1H), 7.88-7.80 (m, 3H), 7.38-6.85 (m,4H), 4.97-4.94 (m, 2H), 3.85 (s, 3H), 2.96-2.94 (m, 2H), 1.93-1.64 (m,6H), 1.47 (s, 9H).

10. Synthesis of4-(5-amino-6,7,8,9-tetrahydro-5H-benzo[7]annulen-2-yl)-N-(1-methyl-1H-pyrazol-4-yl)pyrimidin-2-amine

A mixture of tert-butyl(2-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl)carbamate(240 mg, 0.55 mmol) in TFA (4.0 mL) and CH₂Cl₂ (4.0 mL) was stirred atrt for 2 h. Then the reaction mixture was concentrated to give compound4-(5-amino-6,7,8,9-tetrahydro-5H-benzo[7]annulen-2-yl)-N-(1-methyl-H-pyrazol-4-yl)pyrimidin-2-amine(250 mg, crude) as a yellow oil, which was used in the next step withoutfurther purification. ESI-MS (M+H)⁺: 335.3.

11. Synthesis of5-(tert-butyl)-N-(2-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl)-1,2,4-oxadiazole-3-carboxamide

Synthesis of5-(tert-butyl)-N-(2-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl)-1,2,4-oxadiazole-3-carboxamidewas similar to that of tert-butyl8-bromo-5-(5-(tert-butyl)-1,2,4-oxadiazole-3-carboxamido)-4,5-dihydro-1H-benzo[c]azepine-2(3H)-carboxylatein Example 2. The residue was purified by prep-HPLC (CH₃CN/H₂O with0.05% NH₄HCO₃ as mobile phase) to give5-(tert-butyl)-N-(2-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl)-1,2,4-oxadiazole-3-carboxamideas a yellow solid (120 mg, yield: 42%). ESI-MS (M+H)⁺: 487.3. ¹H NMR(400 MHz, CD₃OD) δ: 8.43 (d, J=5.2 Hz, 1H), 7.98-7.96 (m, 2H), 7.51-7.30(m, 3H), 6.74 (d, J=2.4 Hz, 1H), 5.44 (d, J=10.0 Hz, 1H), 3.83 (s, 3H),3.09-3.03 (m, 2H), 2.10-1.43 (m, 6H), 1.54 (s, 9H).

Example 34.(R)—N-(2-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl)-5-(1-methylcyclopropyl)-1,2,4-oxadiazole-3-carboxamide(compound 34)

1. Synthesis of(R,Z)-5-((1-phenylethyl)imino)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-2-ol

A slurry mixture of2-hydroxy-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-one (Herdman C. A. etal., Structural interrogation of benzosuberen-based inhibitors oftubulin polymerization, Bioorganic & Medical Chemistry, 23(24),7497-7520, 2015) (10 g, 57 mmol), (R)-(+)-α-methylbenzylamine (9.0 g, 74mmol), and p-toluenesulfonic acid (0.48 g, 2.84 mmol) in 150 mL toluenewas heated at reflux with a Dean Stark apparatus. After 16 hr, the DeanStark apparatus was removed and reflux was continued until ˜80 mLtoluene was distilled, during which solid crystallized. The mixture wascooled to 0° C., kept at 0° C. for 2 hr, and then filtered to give(R,Z)-5-((1-phenylethyl)imino)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-2-olas a tan solid (after drying—13.5 g, yield: 85%). The crude product wasused for next step without further purification.

2. Synthesis of (R)-5-amino-6,7,8,9-tetrahydro-5H-benzo[7]annulen-2-olacetate

A slurry of(R,Z)-5-((1-phenylethyl)imino)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-2-ol(13.5 g, 48 mmol) in 10:1 EtOAc/MeOH (148 mL) was cooled to −5° C. SolidNaBH₄ (5.45 g, 144 mmol) was added in portions, while maintaining thetemperature under 5° C. The mixture was stirred at −5° C. for 40 min.After 1 hr, water (135 mL) was added, followed by 5N HCl until pH ˜6.The layers were separated, and the aqueous layer was extracted with 135mL EtOAc. The combined organics were washed with brine (100 mL) anddried (Na₂SO₄) and filtered to give a solution of(R)-5-(((R)-1-phenylethyl)amino)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-2-olwhich was carried forward.

To the solution of(R)-5-(((R)-1-phenylethyl)amino)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-2-ol(48 mmol) in EtOAc (˜185 mL) was added acetic acid (5.8 g, 96 mmol). Thesolution was then concentrated and carried forward.

MeOH (200 mL) was added, followed by 10% Pd/C (1.4 g, 10% wt %). Themixture was stirred under an atmosphere of H₂ (50 psi) at 55° C. for 16hr. The mixture was filtered and the filtrate was concentrated. Methyltert-butyl ether (100 mL) was added, followed by petroleum ether (100mL). The mixture was stirred at 25° C. for 2 hr, and filtered. Afterdrying at 50° C., (R)-5-amino-6,7,8,9-tetrahydro-5H-benzo[7]annulen-2-olacetate was isolated (9.9 g, yield: 87% for three steps.

3. Synthesis of tert-butyl(R)-(2-hydroxy-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl)carbamate

To a solution of (R)-5-amino-6,7,8,9-tetrahydro-5H-benzo[7]annulen-2-olacetate (9.9 g, 42 mmol) in dioxane (50 mL) was added aqueous NaHCO₃(1N, 100 mL, 100 mmol) followed by Boc₂O (13.7 g, 63 mmol. The mixturewas stirred at rt overnight. EtOAc (150 mL) was added and the layerswere separated. The aqueous layer was extracted with EtOAc (150 mL). Thecombined organic layers were dried (Na₂SO₄), filtered, and concentrated.MTBE (150 mL) was added, followed by petroleum ether (150 mL). Afterstirring for 2 hr, the mixture was filtered and the filtrate wasconcentrated to give an oil. The crude material was purified by silicagel chromatography to give tert-butyl(R)-(2-hydroxy-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl)carbamate as awhite solid (7.8 g, yield: 67%, ee: 98.5%). ¹H NMR (400 MHz, DMSO-d₆) δ:9.06 (s, 1H), 7.29-7.27 (m, 1H), 6.94 (d, J=8.8 Hz, 1H), 6.49 (s, 2H),4.48 (m, 1H), 2.65 (br s, 2H), 1.99-1.64 (m, 4H), 1.48-1.25 (m, 11H).

4. Synthesis of(R)-5-((tert-butoxycarbonyl)amino)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-2-yltrifluoromethanesulfonate

To a solution of tert-butyl(R)-(2-hydroxy-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl)carbamate (1.0g, 3.6 mmol) and pyridine (570 mg, 7.2 mmol) in DCM (30 mL) was addedTf₂O (1.5 g, 5.4 mmol) at 0° C. The mixture was stirred at 0° C. for 1h. After diluting with water (20 mL), the mixture was extracted with DCM(3×40 mL). The combined organic layers were washed by aq. NaHSO4 (0.5 N,20 mL) to adjust water layer to pH=5-6, dried (Na₂SO₄), filtered andconcentrated. The crude product was used for next step without furtherpurification. ESI-MS (M+H)⁺: 410.1. ¹H NMR (400 MHz, CDCl₃) δ: 7.31 (d,J=8.8 Hz, 1H), 7.07-7.00 (m, 2H), 4.93-4.88 (m, 2H), 2.89-2.82 (m, 2H),1.91-1.68 (m, 6H), 1.45 (s, 9H).

5. Synthesis of tert-butyl(R)-(2-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl)carbamate

Synthesis of tert-butyl(R)-(2-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl)carbamatewas similar to that of tert-butyl5-(5-(tert-butyl)-1,2,4-oxadiazole-3-carboxamido)-8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-4,5-dihydro-1H-benzo[c]azepine-2(3H)-carboxylate(Example 2, Step 11). The crude product was purified by silica gelcolumn chromatograph (DCM/MeOH=20:1) to give tert-butyl(R)-(2-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl)carbamateas a yellow solid (420 mg, yield: 68%). ESI-MS (M+H)⁺: 435.2. ¹H NMR(400 MHz, CDCl₃) δ: 8.41-8.37 (m, 1H), 7.88-7.77 (m, 3H), 7.55-7.36 (m,4H), 7.05 (d, J=5.2 Hz, 1H), 5.09-5.01 (m, 1H), 3.90 (s, 3H), 2.93-2.91(m, 2H), 2.18-2.17 (m, 1H), 1.91-1.82 (m, 5H), 1.28-1.24 (m, 9H).

6. Synthesis of(R)-4-(5-amino-6,7,8,9-tetrahydro-5H-benzo[7]annulen-2-yl)-N-(1-methyl-1H-pyrazol-4-yl)pyrimidin-2-amine

Synthesis of(R)-4-(5-amino-6,7,8,9-tetrahydro-5H-benzo[7]annulen-2-yl)-N-(1-methyl-1H-pyrazol-4-yl)pyrimidin-2-aminewas similar to5-(tert-butyl)-N-(8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1,2,4-oxadiazole-3-carboxamidedescribed in Example 2, Step 12. The crude product was used for nextstep without further purification. ESI-MS (M+H)⁺: 335.2.

7. Synthesis of ethyl(Z)-2-amino-2-(((1-methylcyclopropane-1-carbonyl)oxy)imino)acetate

To a solution of 1-methylcyclopropane-1-carboxylic acid (2 g, 20 mmol)in DCM (50 mL) was added (COCl)₂ (5 g, 40 mmol). The mixture was stirredat rt for 16 h and then concentrated to give the intermediate acylchloride. To a solution of ethyl (Z)-2-amino-2-(hydroxyimino)acetate(2.6 g, 20 mmol) and triethylamine (6 g, 60 mmol) in DCM (20 mL) wasadded a solution of the intermediate acyl chloride in DCM (20 mL). Thereaction was stirred at rt for 2 h, washed by water, dried by Na₂SO₄,concentrated to give ethyl(Z)-2-amino-2-(((1-methylcyclopropane-1-carbonyl)oxy)imino)acetate as awhite solid (3.0 g, yield: 63%). ESI-MS (M+H)⁺: 215.1.

8. Synthesis of ethyl5-(1-methylcyclopropyl)-1,2,4-oxadiazole-3-carboxylate

A solution of ethyl(Z)-2-amino-2-(((1-methylcyclopropane-1-carbonyl)oxy)imino)acetate (3.0g, 14 mmol) in AcOH (20 mL) was stirred at 100° C. for 2 h and thenconcentrated. The residue was diluted with DCM (20 mL), washed bysaturated NaHCO₃ solution (3×10 mL), dried over Na₂SO₄, andconcentrated. The residue was purified by silica gel column (petroleumether:EtOAc=10:1) to give ethyl5-(1-methylcyclopropyl)-1,2,4-oxadiazole-3-carboxylate as a yellow solid(1.1 g, yield: 52%). ESI-MS (M+H)⁺: 197.1.

9. Synthesis of potassium5-(1-methylcyclopropyl)-1,2,4-oxadiazole-3-carboxylate

Ethyl 5-(1-methylcyclopropyl)-1,2,4-oxadiazole-3-carboxylate (1.0 g, 5.0mmol) and KOH (308 mg, 5.5 mmol) was dissolved in EtOH/H₂O (4:1, 20 mL).The reaction was stirred at rt for 12 h and then concentrated to givepotassium 5-(1-methylcyclopropyl)-1,2,4-oxadiazole-3-carboxylate as ayellow solid (1.1 g, yield: 95%). ESI-MS (M+H)⁺: 169.1.

10. Synthesis ofN-(2-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl)-5-(1-methylcyclopropyl)-1,2,4-oxadiazole-3-carboxamide(I-IM_6)

To a solution of potassium5-(1-methylcyclopropyl)-1,2,4-oxadiazole-3-carboxylate (123 mg, 0.6mmol), DIPEA (232 mg, 0.75 mmol) and HATU (342 mg, 0.9 mmol) in DCM (5mL) was added(R)-4-(5-amino-6,7,8,9-tetrahydro-5H-benzo[7]annulen-2-yl)-N-(1-methyl-1H-pyrazol-4-yl)pyrimidin-2-amine(150 mg, 0.50 mmol). The mixture was stirred at rt for 1 h. Afterdiluted with water (60 mL), the mixture was extracted with DCM (80mL×2). The combined organic layers were dried and concentrated. Thecrude product was purified by prep-HPLC to give(R)—N-(2-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl)-5-(1-methylcyclopropyl)-1,2,4-oxadiazole-3-carboxamideas a white solid (60 mg, yield: 30%). ESI-MS (M+H)⁺: 485.2. ¹H NMR (400MHz, CD₃OD) δ: 8.40 (d, J=5.2 Hz, 1H), 7.97 (s, 1H), 7.98-7.93 (m, 2H),7.66 (s, 1H), 7.39 (d, J=8.4 Hz, 1H), 7.21 (d, J=5.2 Hz, 1H), 5.43 (d,J=10 Hz, 1H), 3.90 (s, 3H), 3.09-3.02 (m, 2H), 2.09-1.86 (m, 5H), 1.64(s, 3H), 1.54-1.45 (m, 3H), 1.21-1.18 (m, 2H).

Example 35.(R)-5-(tert-butyl)-N-(2-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyridin-4-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl)-1,2,4-oxadiazole-3-carboxamide(compound 35)

1. Synthesis of tert-butyl(R)-(2-(2-chloropyridin-4-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl)carbamate

Synthesis of tert-butyl(R)-(2-(2-chloropyridin-4-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl)carbamatewas similar to that of tert-butyl1-(5-(tert-butyl)-1,2,4-oxadiazole-3-carboxamido)-7-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-4,5-dihydro-1H-benzo[d]azepine-3(2H)-carboxylate(Example 1, Step 12). The crude was purified by silica gel columnchromatography (MeOH/EtOAc=1/50) to give tert-butyl(R)-(2-(2-chloropyridin-4-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl)carbamateas a yellow solid (350 mg, yield: 44%). ESI-MS (M+H)⁺: 373.2.

2. Synthesis of tert-butyl(R)-(2-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyridin-4-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl)carbamate

To a solution of tert-butyl(R)-(2-(2-chloropyridin-4-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl)carbamate(400 mg, 1.1 mmol) in dioxane (20 mL) were added1-methyl-1H-pyrazol-4-amine (210 mg, 2.1 mmol), Pd₂(dba)₃ (100 mg, 0.11mmol), SPhos (45 mg, 0.11 mmol) and Cs₂CO₃ (680 mg, 2.1 mmol). Themixture was heated to 100° C. for 2 h and concentrated. The crude waspurified by silica gel column chromatography (MeOH/EtOAc=1/50) to givetert-butyl(R)-(2-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyridin-4-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl)carbamate(330 mg, yield: 71%) as a yellow solid. ESI-MS (M+H)⁺: 434.2.

3. Synthesis of(R)-4-(5-amino-6,7,8,9-tetrahydro-5H-benzo[7]annulen-2-yl)-N-(1-methyl-1H-pyrazol-4-yl)pyridin-2-amine

Synthesis of(R)-4-(5-amino-6,7,8,9-tetrahydro-5H-benzo[7]annulen-2-yl)-N-(1-methyl-1H-pyrazol-4-yl)pyridin-2-aminewas similar to that of5-(tert-butyl)-N-(7-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-1-yl)-1,2,4-oxadiazole-3-carboxamide(Example 1, Step 13). The crude product(R)-4-(5-amino-6,7,8,9-tetrahydro-5H-benzo[7]annulen-2-yl)-N-(1-methyl-1H-pyrazol-4-yl)pyridin-2-aminewas obtained as yellow solid (200 mg, yield: 79%). ESI-MS (M+H)⁺: 334.2.

4. Synthesis of(R)-5-(tert-butyl)-N-(2-(2-((1-methyl-H-pyrazol-4-yl)amino)pyridin-4-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl)-1,2,4-oxadiazole-3-carboxamide(I-IM_65)

Synthesis of(R)-5-(tert-butyl)-N-(2-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyridin-4-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl)-1,2,4-oxadiazole-3-carboxamidewas similar toN-(2-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl)-5-(1-methylcyclopropyl)-1,2,4-oxadiazole-3-carboxamidedescribed in Example 34, Step 10. The mixture was purified by prep-HPLC(CH₃CN/H₂O with 0.05% NH₃.H₂O as mobile phase) to give(R)-5-(tert-butyl)-N-(2-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyridin-4-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl)-1,2,4-oxadiazole-3-carboxamideas yellow solid (100 mg, yield: 88%). ESI-MS (M+H)⁺: 486.3. ¹H NMR (400MHz, CDCl₃) δ: 8.17-8.16 (m, 1H), 7.61 (s, 1H), 7.48 (s, 1H), 7.43-7.41(m, 1H), 7.36-7.30 (m, 3H), 6.87-6.86 (m, 1H), 6.71 (s, 1H), 6.22-6.18(m, 1H), 5.44-5.40 (m, 1H), 3.91 (s, 3H), 3.01-2.89 (m, 2H), 2.05-1.93(m, 4H), 1.82-1.78 (m, 2H), 1.49 (s, 9H).

Example 36.(R)-5-(tert-butyl)-N-(2-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl)-1,3,4-oxadiazole-2-carboxamide(compound 36a)

1. Synthesis of(R)-1-(tert-butyl)-N-(8-(2-chloropyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1H-1,2,3-triazole-4-carboxamide

Synthesis of(R)-1-(tert-butyl)-N-(8-(2-chloropyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1H-1,2,3-triazole-4-carboxamidewas similar to that of(R)-5-(tert-butyl)-N-(8-(2-((1,5-dimethyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1,2,4-oxadiazole-3-carboxamide(Example 9, Step 4). The crude product was used for next step withoutpurification. ESI-MS (M+H)⁺: 427.2.

2. Synthesis of(R)-5-(tert-butyl)-N-(2-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl)-1,3,4-oxadiazole-2-carboxamide(compound 36a) and(S)-5-(tert-butyl)-N-(2-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl)-1,3,4-oxadiazole-2-carboxamide(compound 36b)

3-tert-Butyl-1,2,4-oxadiazole-5-carboxylic acid{2-[2-(1-methyl-1H-pyrazol-4-ylamino)-pyrimidin-4-yl]-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-yl}-amide(76 mg) was subjected to SFC separation (IA 2×(2×15 cm), 30%ethanol/CO₂, 100 bar, 70 mL/min, 220 nm, inj vol.: 1 mL, 5 mg/mL,ethanol) and yielded 43 mg of peak-1 (chemical purity 99%, ee>99%) and36 mg of peak-2 (chemical purity 99%, ee>99%).

Peak 1 is assigned as(R)-5-(tert-butyl)-N-(2-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl)-1,3,4-oxadiazole-2-carboxamide:LCMS: Rt 1.23 min, m/z 487.00. ¹H NMR (400 MHz, METHANOL-d4) δ 8.41 (d,J=5.27 Hz, 1H), 7.96 (d, J=11.80 Hz, 3H), 7.66 (s, 1H), 7.43 (d, J=8.53Hz, 1H), 7.22 (d, J=5.27 Hz, 1H), 5.43 (d, J=9.29 Hz, 1H), 3.90 (s, 3H),2.96-3.24 (m, 2H), 1.74-2.25 (m, 5H), 1.51 (s, 9H), 1.28-1.43 (m, 1H).

Peak 2 is assigned as(S)-5-(tert-butyl)-N-(2-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl)-1,3,4-oxadiazole-2-carboxamide:LCMS: Rt 1.23 min, m/z 487.00. ¹H NMR (400 MHz, METHANOL-d4) δ 8.40 (d,J=5.27 Hz, 1H), 7.96 (d, J=12.05 Hz, 3H), 7.66 (s, 1H), 7.43 (d, J=8.53Hz, 1H), 7.22 (d, J=5.27 Hz, 1H), 5.44 (s, 1H), 3.90 (s, 3H), 2.93-3.21(m, 2H), 1.78-2.23 (m, 5H), 1.51 (s, 9H), 1.31 (s, 1H).

Example 37.3-(tert-butyl)-N-(2-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl)-1,2,4-oxadiazole-5-carboxamide(compound 37)

To a solution of 3-tert-butyl-1,2,4-oxadiazole-5-carboxylic acid (1.00mg, 0.60 mmol) andN,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uroniumhexafluorophosphate (273 mg, 0.72 mmol) and4-(5-amino-6,7,8,9-tetrahydro-5H-benzo[7]annulen-2-yl)-N-(1-methyl-1H-pyrazol-4-yl)pyrimidin-2-amine(200 mg, 0.6 mmol) in N,N-dimethylformamide (2.3 mL) was addedN,N-diisopropylethylamine (0.42 mL, 2.4 mmol). The reaction was stirredat rt overnight and was quenched with MeOH. After workup, prep HPLC gave3-(tert-butyl)-N-(2-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl)-1,2,4-oxadiazole-5-carboxamideas a solid (186 mg; yield: 64%). LCMS: Rt 1.38 min.; m/z 487.1; 1H NMR(400 MHz, METHANOL-d4) δ: 8.29 (br. s., 1H), 7.97-8.09 (m, 2H), 7.94 (s,1H), 7.68 (br. s., 1H), 7.43 (d, J=8.78 Hz, 2H), 5.41 (d, J=9.79 Hz,1H), 3.92 (s, 3H), 2.87-3.18 (m, 2H), 1.70-2.29 (m, 5H), 1.45 (s, 10H).

Example 38:5-(tert-butyl)-N-(8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydrobenzo[b]oxepin-5-yl)-1,3,4-oxadiazole-2-carboxamide(compound 38)

1. Synthesis of methyl 4-(3-bromophenoxy)butanoate

To a solution of 3-bromophenol (3.44 g, 20.0 mmol) and methyl4-bromobutanoate (4.32 g, 24.0 mmol) in DMF (20 mL) was added K₂CO₃(5.52 g, 40.0 mmol). The mixture was stirred at rt for 0.5 h and thenheated with stirring at 90° C. for 1 h. After diluting with EtOAc (200mL), the mixture was washed with water (3×50 mL), dried andconcentrated. The crude product was purified by silica gel columnchromatograph (petroleum/EtOAc=10:1) to give methyl4-(3-bromophenoxy)butanoate as a white liquid (5.2 g, yield: 96%).ESI-MS (M+H)⁺: 273.1.

2. Synthesis of 4-(3-bromophenoxy)butanoic acid

To a solution of methyl 4-(3-bromophenoxy)butanoate (4.9 g, 19 mmol) inMeOH (40 mL) and H₂O (40 mL) was added NaOH (2.3 g, 57 mmol). Thereaction mixture was stirred at 65° C. for 1 h. Then the solvent wasconcentrated under reduced pressure. The residue was adjusted to pH=3with HCl (1 N). The mixture was extracted with EtOAc (3×100 mL×3). Theorganic layers were dried over sodium sulfate and concentrated underreduced pressure to give 4-(3-bromophenoxy)butanoic acid (4.8 g, yield:98%). The crude product was used in next step without furtherpurification. ESI-MS (M+H)⁺: 259.1. ¹H NMR (400 MHz, CDCl₃) δ: 7.24-7.20(m, 1H), 7.10-7.08 (m, 2H), 6.93 (d, J=9.6 Hz, 1H), 3.97 (t, J=6.4 Hz,2H), 2.35 (t, J=7.2 Hz, 2H), 1.92-1.88 (m, 2H).

3. Synthesis of 8-bromo-3,4-dihydrobenzo[b]oxepin-5(2H)-one

To a solution of 4-(3-bromophenoxy)butanoic acid (1.82 g, 7.04 mmol) inDCM (35 mL) was added SOCl₂ (1.67 g, 14 mmol) and DMF (cat.). Thereaction mixture was stirred at 40° C. for 1 h. Then the solvent wasremoved under reduced pressure, dried in vacuo for 2 h. The residue wasdissolved in DCM (35 mL) and cooling down with an ice bath. AlCl₃ (1.02g, 80 mmol) was added and the mixture was stirred at 0° C.-rt for 12 h.The mixture was poured into con. HCl (10 mL) and extracted with EtOAc(2×50 mL). The organic layers were washed with water (50 mL), brine (50mL) and dried over sodium sulfate. After concentration under reducedpressure, the crude product was purified by silica gel columnchromatograph (petroleum ether/EtOAc=4:1) to give8-bromo-3,4-dihydrobenzo[b]oxepin-5(2H)-one as a white solid (1.2 g,yield: 71%). ESI-MS (M+H)⁺: 241.1. ¹H NMR (400 MHz, CDCl₃) δ: 7.64 (d,J=8.8 Hz, 1H), 7.27-7.23 (m, 2H), 4.25 (t, J=6.8 Hz, 2H), 2.89 (t, J=7.2Hz, 2H), 2.25-2.18 (m, 2H).

4. Synthesis of 8-bromo-2,3,4,5-tetrahydrobenzo[b]oxepin-5-amine

To a mixture of 8-bromo-3,4-dihydrobenzo[b]oxepin-5(2H)-one (1.2 g, 5.0mmol) in i-PrOH (50 mL), NH₄OAc (7.63 g, 100 mmol) and NaBH₃CN (3.15 g,50 mol) was added. The mixture was stirred at 80° C. for 4 h. Aftercooling down, the mixture was basified to pH>12 with NaOH (1 N). Themixture was extracted with DCM (250 mL×2). The combined organic layerswere dried and concentrated. The resulting residue was purified bysilica gel column (DCM:MeOH=20:1) to give8-bromo-2,3,4,5-tetrahydrobenzo[b]oxepin-5-amine as a white solid (900mg, yield: 75%) was obtained. ESI-MS (M+H —NH₃)⁺: 225.1.

5. Synthesis ofN-(8-bromo-2,3,4,5-tetrahydrobenzo[b]oxepin-5-yl)-5-(tert-butyl)-1,3,4-oxadiazole-2-carboxamide

To a solution of 8-bromo-2,3,4,5-tetrahydrobenzo[b]oxepin-5-amine (500mg, 2.23 mmol, 1.0 eq) in DMF (20 mL), potassium5-tert-butyl-1,3,4-oxadiazole-2-carboxylate (557 mg, 2.68 mmol, 1.2 eq),HATU (1.3 g, 3.35 mmol, 1.5 eq) and triethylamine (863 mg, 6.69 mmol,3.0 eq) were added. The mixture was stirred at rt for 2 h. The solutionwas diluted with EtOAc (150 mL) and washed with water (50 mL), brine(2×50 mL). The organic layer was dried (Na₂SO₄), filtered, andconcentrated via rotary evaporator. The residue was purified by reversephase chromatography (CH₃CN/H₂O with 0.05% NH₃.H₂O as mobile phase) togiveN-(8-bromo-2,3,4,5-tetrahydrobenzo[b]oxepin-5-yl)-5-(tert-butyl)-1,3,4-oxadiazole-2-carboxamide(210 mg, yield: 30%) as a slight yellow solid. ESI-MS (M+H)⁺: 394.1.

6. The Preparation of5-(tert-butyl)-N-(8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydrobenzo[b]oxepin-5-yl)-1,3,4-oxadiazole-2-carboxamide

To a mixture ofN-(8-bromo-2,3,4,5-tetrahydrobenzo[b]oxepin-5-yl)-5-(tert-butyl)-1,3,4-oxadiazole-2-carboxamide(393 mg, 1.00 mmol) and PinB-BPin (263 mg, 1.1 mmol) in dry 1,4-dioxane(10 mL), KOAc (196 mg, 2.0 mmol), Pd(dppf)Cl₂.DCM (81 mg, 0.1 mmol) wasadded under N₂. The mixture was stirred at 100° C. for 2 h under N₂.After cooling down,4-chloro-N-(1-methyl-1H-pyrazol-4-yl)pyrimidin-2-amine (209 mg, 1.0mmol), K₂CO₃ (276 mg, 2.0 mmol) and H₂O (2.5 mL) was added. The mixturewas stirred at 100° C. for 2 h under N₂. After cooling down, the mixturewas concentrated and purified silica gel column chromatograph(DCM/MeOH=20:1) to give5-(tert-butyl)-N-(8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydrobenzo[b]oxepin-5-yl)-1,3,4-oxadiazole-2-carboxamideas yellow solid (50 mg, yield: 21%). ESI-MS (M+H)⁺: 489.2. ¹H NMR (400MHz, CD₃OD) δ:8.26 (d, J=5.2 Hz, 1H), 7.82 (s, 1H), 7.69-7.64 (m, 2H),7.51 (s, 1H), 7.29 (d, J=8.0 Hz, 1H), 7.02 (d, J=5.2 Hz, 1H), 5.35-5.32(m, 1H), 4.14-4.10 (m, 1H), 3.83-3.80 (m, 1H), 3.76 (s, 3H), 2.00-1.98(m, 4H), 1.36 (s, 9H).

Example 39. Synthesis of5-(tert-butyl)-N-(8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydrobenzo[b]oxepin-5-yl)-1,2,4-oxadiazole-2-carboxamide(compound 39)

1. Synthesis ofN-(8-bromo-2,3,4,5-tetrahydrobenzo[b]oxepin-5-yl)-5-(tert-butyl)-1,2,4-oxadiazole-2-carboxamide

Synthesis ofN-(8-bromo-2,3,4,5-tetrahydrobenzo[b]oxepin-5-yl)-5-(tert-butyl)-1,2,4-oxadiazole-3-carboxamidewas similar to that of tert-butyl(R)-8-bromo-5-(5-(tert-butyl)-1,2,4-oxadiazole-3-carboxamido)-1,3,4,5-tetrahydro-2H-benzo[c]azepine-2-carboxylatein Example 2, Method 2, Step 2. The crude material was purified bysilica gel chromatography (PE:EtOAc=3:1) to giveN-(8-bromo-2,3,4,5-tetrahydrobenzo[b]oxepin-5-yl)-5-(tert-butyl)-1,2,4-oxadiazole-2-carboxamide(610 mg, yield: 85%) as a slight yellow solid. ESI-MS (M+H)⁺: 394.1.

2. The Preparation of5-(tert-butyl)-N-(8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydrobenzo[b]oxepin-5-yl)-1,2,4-oxadiazole-2-carboxamide

To a mixture ofN-(8-bromo-2,3,4,5-tetrahydrobenzo[b]oxepin-5-yl)-5-(tert-butyl)-1,2,4-oxadiazole-2-carboxamide(135 mg, 0.34 mmol) and PinB-BPin (96 mg, 0.38 mmol) in dry 1,4-dioxane(3 mL), KOAc (68 mg, 0.69 mmol), Pd(dppf)Cl₂.DCM (24 mg, 0.03 mmol) wasadded under N₂. The mixture was stirred at 100° C. for 2 h under N₂.After cooling down,4-chloro-N-(1-methyl-1H-pyrazol-4-yl)pyrimidin-2-amine (71 mg, 0.34mmol), K₂CO₃ (95 mg, 0.69 mmol) and H₂O (0.8 mL) was added. The mixturewas stirred at 100° C. for 2 h under N₂. After cooling down, the mixturewas concentrated and purified by silica gel chromatography(DCM:MeOH=20:1) to give5-(tert-butyl)-N-(8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydrobenzo[b]oxepin-5-yl)-1,2,4-oxadiazole-2-carboxamideas yellow solid (77 mg, yield: 46%). ESI-MS (M+H)⁺: 489.2. ¹H NMR (400MHz, CD₃OD) δ: 8.35 (d, J=5.2 Hz, 1H), 7.91 (s, 1H), 7.78-7.73 (m, 2H),7.62 (s, 1H), 7.38 (d, J=8.4 Hz, 1H), 7.10 (d, J=5.6 Hz, 1H), 5.46-5.44(m, 1H), 4.18-4.15 (m, 1H), 3.98-3.95 (m, 1H), 3.86 (s, 3H), 2.10-2.02(m, 4H), 1.48 (s, 9H).

Example 40.5-(tert-butyl)-N-(3-(2-((1-methyl-H-pyrazol-4-yl)amino)pyrimidin-4-yl)-6,7,8,9-tetrahydro-5H-cyclohepta[c]pyridin-9-yl)-1,3,4-oxadiazole-2-carboxamide(compound 40)

1. Synthesis of 3-chlorocyclohept-2-en-1-one

To a solution of cycloheptane-1,3-dione (20.0 g, 0.16 mol) and DMF (11.6g, 0.16 mol) in DCM (500 mL) was added oxalyl chloride (24.4 g, 0.19mol) dropwise at 0° C. After stirring at 0° C. for 30 min, the reactionmixture was washed with water (3×500 mL). The aqueous phase was thenextracted with diethyl ether (4×300 mL). The combined DCM and diethylether phases were dried over MgSO₄ and concentrated to yield3-chlorocyclohept-2-en-1-one (crude 22.8 g, used for next step) as abrown oil. ESI-MS (M+H)⁺: 145.1.

2. Synthesis of 2-cyano-2-(3-oxocyclohept-1-en-1-yl)acetamide

To a solution of 2-cyanoacetamide (26.9 g, 0.32 mol) in DMF (300 mL) wasadded NaH (60 percent in mineral oil, 14.1 g, 0.35 mol) in one portionat 0° C. After stirring at 0° C. for 30 min, a solution of3-chlorocyclohept-2-en-1-one (22.8 g, 0.16 mol) in DMF (100 mL) wasadded dropwise. The reaction mixture was stirred at room temperature for30 min and DMF was removed under reduced pressure. The residue wasdissolved in water (350 mL). The solution was washed with ethyl acetate(4×150 mL), adjusted with 3.0 N aqueous HCl to pH 2-3 and extracted with10% MeOH/DCM (6×300 mL). The latter combined extracts were dried overMgSO₄ and concentrated. The crude product was purified by silica gelcolumn chromatography (EtOAc/petroleum ether=4:1) to give2-cyano-2-(3-oxocyclohept-1-en-1-yl)acetamide as yellow oil (22.0 g,yield: 73% for two steps). ESI-MS (M+H)⁺: 193.1.

3. Synthesis of3,9-dioxo-3,5,6,7,8,9-hexahydro-2H-cyclohepta[c]pyridine-4-carbonitrile

To a solution of 2-cyano-2-(3-oxocyclohept-1-en-1-yl)acetamide (22.0 g,0.11 mol) in DMF (150 mL) was added DMF-DMA (22.8 mL, 0.17 mol) dropwiseover 0.5 h. The reaction mixture was stirred at 50° C. for 4 h andconcentrated under reduced pressure. The resulting brown oil wasdissolved in aqueous NaOH (1.0 N, 200 mL), washed with chloroform (5×150mL) and acidified with HCl (6.0 N) slowly at 0° C. to pH 2-3. The brownsolid,3,9-dioxo-3,5,6,7,8,9-hexahydro-2H-cyclohepta[c]pyridine-4-carbonitrile(17.0 g, yield: 74%), was collected by filtration and dried in vacuo.ESI-MS (M+H)⁺: 203.1. ¹H NMR (400 MHz, CDCl₃) δ: 8.16 (s, 1H), 3.17-3.14(m, 2H), 2.77-2.74 (m, 2H), 2.04-2.00 (m, 2H), 1.90-1.87 (m, 2H).

4. Synthesis of 5,6,7,8-tetrahydro-2H-cyclohepta[c]pyridine-3,9-dione

A solution of3,9-dioxo-3,5,6,7,8,9-hexahydro-2H-cyclohepta[c]pyridine-4-carbonitrile(17.0 g, 0.084 mol) in 50 percent conc. sulfuric acid (100 mL) wasstirred at 140° C. for 12 h. The reaction mixture was neutralized with50 percent sodium hydroxide slowly at 0° C. to pH 7-8. The water wasremoved under reduced pressure. The residue was dissolved into warmchloroform and an insoluble solid was removed by filtration. Thefiltrate was concentrated and purified by silica gel columnchromatograph (DCM/MeOH=20:1) to give5,6,7,8-tetrahydro-2H-cyclohepta[c]pyridine-3,9-dione as a yellow solid(9.5 g, yield: 63%). ESI-MS (M+H)⁺: 178.1.

5. Synthesis of9-amino-2,5,6,7,8,9-hexahydro-3H-cyclohepta[c]pyridin-3-one

A mixture of 5,6,7,8-tetrahydro-2H-cyclohepta[c]pyridine-3,9-dione (7.0g, 39.5 mmol), NH₄OAc (60.8 g, 790.0 mmol), and NaBH₃CN (7.4 g, 118.5mmol) in i-PrOH (150 mL) was heated to 80° C. for 8 h and cooled to rt.The solution was used for next step without purification. ESI-MS (M+H)⁺:179.2.

6. Synthesis of tert-butyl(3-oxo-3,5,6,7,8,9-hexahydro-2H-cyclohepta[c]pyridin-9-yl)carbamate

To the previous solution was added NaHCO₃ (aq, 50 mL), THF (50 mL) andBoc₂O (17.2 g, 79.0 mmol). The mixture was stirred at rt for 6 h. Afterconcentration and diluting with water (100 mL), the mixture wasextracted with DCM (3×200 mL). The combined organic layers were washedwith brine (200 mL), dried (Na₂SO₄), filtered and concentrated. Thecrude product was purified by silica gel column chromatograph(DCM/MeOH=20:1) to give tert-butyl(3-oxo-3,5,6,7,8,9-hexahydro-2H-cyclohepta[c]pyridin-9-yl)carbamate asyellow solid (6.2 g, yield: 56% for two steps). ESI-MS (M+H)⁺: 279.2. ¹HNMR (400 MHz, CDCl₃) δ: 7.25 (s, 1H), 6.35 (s, 1H), 5.30 (brs, 1H),2.65-2.63 (m, 2H), 1.86-1.76 (m, 4H), 1.45 (s, 9H), 1.39-1.35 (m, 2H).

7. Synthesis of9-((tert-butoxycarbonyl)amino)-6,7,8,9-tetrahydro-5H-cyclohepta[c]pyridin-3-yltrifluoromethanesulfonate

To a solution of tert-butyl(3-oxo-3,5,6,7,8,9-hexahydro-2H-cyclohepta[c]pyridin-9-yl)carbamate (6.2g, 22.3 mmol) and triethylamine (6.8 g, 66.9 mmol) in DCM (150 mL) at 0°C. was added Tf₂O (9.4 g, 33.5 mmol) dropwise. The mixture was stirredfor 1 h. The solution was diluted with water (150 mL), extracted withDCM (2×200 mL). The combined organic layers were washed with brine,dried over Na₂SO₄, filtered, and concentrated. The crude product waspurified by silica gel column chromatograph (petroleum ether/EtOAc=4:1)to give9-((tert-butoxycarbonyl)amino)-6,7,8,9-tetrahydro-5H-cyclohepta[c]pyridin-3-yltrifluoromethanesulfonate as a yellow solid (5.7 g, Y: 63%). ESI-MS(M+H)⁺: 411.1.

8. Synthesis of tert-butyl(3-(1-ethoxyvinyl)-6,7,8,9-tetrahydro-5H-cyclohepta[c]pyridin-9-yl)carbamate

A mixture of9-((tert-butoxycarbonyl)amino)-6,7,8,9-tetrahydro-5H-cyclohepta[c]pyridin-3-yltrifluoromethanesulfonate (2.4 g, 5.85 mmol),tributyl(1-ethoxyvinyl)stannane (4.3 g, 11.7 mmol), triethylamine (1.8g, 17.6 mmol), Pd(OAc)₂ (131 mg, 0.58 mmol) and dppp (903 mg, 2.34 mmol)in 50 mL DMF was stirred at 70° C. for 2 h under nitrogen in sealedtube. The mixture was diluted with EtOAc (200 mL) and washed with water(3×100 mL). The organic phase was dried with Na₂SO₄ and concentrated.The crude product was purified by silica gel column chromatograph(petroleum ether/EtOAc=4:1) to give tert-butyl(3-(1-ethoxyvinyl)-6,7,8,9-tetrahydro-5H-cyclohepta[c]pyridin-9-yl)carbamateas a yellow solid (1.0 g, yield: 51%). ESI-MS (M+H)⁺: 333.2.

9. Synthesis of1-(9-amino-6,7,8,9-tetrahydro-5H-cyclohepta[c]pyridin-3-yl)ethan-1-one

To a solution of tert-butyl(3-(1-ethoxyvinyl)-6,7,8,9-tetrahydro-5H-cyclohepta[c]pyridin-9-yl)carbamate(1.0 g, 3.0 mmol) in THF (30 mL) was added HCl (1 mL, 6.0 mmol)dropwise. The mixture was stirred at rt for 1 h. The solution was usedfor next step without purification. ESI-MS (M+H)⁺: 205.1.

10. Synthesis of tert-butyl(3-acetyl-6,7,8,9-tetrahydro-5H-cyclohepta[c]pyridin-9-yl)carbamate

Synthesis of tert-butyl(3-acetyl-6,7,8,9-tetrahydro-5H-cyclohepta[c]pyridin-9-yl)carbamate wassimilar to that of tert-butyl(3-oxo-3,5,6,7,8,9-hexahydro-2H-cyclohepta[c]pyridin-9-yl)carbamate(Example 40, Step 6). The crude product was purified by silica gelcolumn chromatograph (petroleum ether/EtOAc=4:1) to give tert-butyl(3-acetyl-6,7,8,9-tetrahydro-5H-cyclohepta[c]pyridin-9-yl)carbamate as ayellow solid (550 mg, yield: 60% for two steps). ESI-MS (M+H)⁺: 305.2.¹H NMR (400 MHz, CDCl₃) δ: 8.54 (s, 1H), 7.78 (s, 1H), 4.99-4.97 (m,2H), 2.91-2.90 (m, 2H), 2.70 (s, 3H), 1.94-1.74 (m, 4H), 1.62-1.60 (m,2H), 1.45 (s, 9H).

11. Synthesis of tert-butyl(3-(3-(dimethylamino)acryloyl)-6,7,8,9-tetrahydro-5H-cyclohepta[c]pyridin-9-yl)carbamate

A solution of tert-butyl(3-acetyl-6,7,8,9-tetrahydro-5H-cyclohepta[c]pyridin-9-yl)carbamate (550mg, 1.8 mmol) in DMF-DMA (10 mL) was stirred at 100° C. for 2 h. Afterconcentration, the crude product was purified by reversed phase HPLC(CH₃CN/0.05% NH₃.H₂O in water) to give tert-butyl(3-(3-(dimethylamino)acryloyl)-6,7,8,9-tetrahydro-5H-cyclohepta[c]pyridin-9-yl)carbamate(380 mg, yield: 61%). ESI-MS (M+H)⁺: 360.2.

12. Synthesis of 1-(1-methyl-1H-pyrazol-4-yl)guanidine hydrochloride

To a solution of 1-methyl-1H-pyrazol-4-amine (500 mg, 5 mmol, 1.0 eq) indioxane (10 mL) was added cyanamide (273 g, 6.5 mmol, 1.3 eq) and conc.HCl (1 mL). The reaction was stirred at 100° C. for 12 h. The solventwas removed under reduced pressure. The residue was recrystallized fromthe co-solvent of MeOH and Et₂O. 1-(1-methyl-1H-pyrazol-4-yl)guanidinehydrochloride (600 mg, yield: 55%) was obtained as a yellow solid.ESI-MS (M+H)⁺: 140.1. ¹H NMR (400 MHz, CD₃OD) δ: 7.78 (s, 1H), 7.48 (s,1H), 3.91 (s, 3H).

13. Synthesis of tert-butyl(3-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-6,7,8,9-tetrahydro-5H-cyclohepta[c]pyridin-9-yl)carbamate

A mixture of 1-(1-methyl-1H-pyrazol-4-yl)guanidine hydrochloride (588mg, 4.23 mmol), K₂CO₃ (1.2 g, 8.46 mmol), and triethylamine (855 mg,8.46 mmol) in EtOH (10 mL) was stirred at rt for 1 h, then tert-butyl(3-(3-(dimethylamino)acryloyl)-6,7,8,9-tetrahydro-5H-cyclohepta[c]pyridin-9-yl)carbamate(380 mg, 1.06 mmol) was added and the mixture was heated to 90° C. for12 h. After concentration, the crude product was purified by reversedphase HPLC (CH₃CN/0.05% NH₃.H₂O in water) to give tert-butyl(3-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-6,7,8,9-tetrahydro-5H-cyclohepta[c]pyridin-9-yl)carbamate(240 mg, yield: 52%). ESI-MS (M+H)⁺: 436.2. ¹H NMR (400 MHz, CDCl₃) δ:8.57 (s, 1H), 8.50 (d, J=5.2 Hz, 1H), 8.08 (s, 1H), 7.85 (s, 1H), 7.66(d, J=5.6 Hz, 1H), 7.60 (s, 1H), 6.92 (s, 1H), 5.00 (br, 2H), 3.92 (s,3H), 2.97-2.90 (m, 2H), 2.01-1.82 (m, 5H), 1.51-1.46 (m, 10H).

14. Synthesis of3-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-6,7,8,9-tetrahydro-5H-cyclohepta[c]pyridin-9-amine

To a solution of tert-butyl(3-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-6,7,8,9-tetrahydro-5H-cyclohepta[c]pyridin-9-yl)carbamate(240 mg, 0.55 mmol) in DCM (5 mL) was added TFA (5 mL). The mixture wasstirred at rt for 1 h. After concentration, the residue was basifiedwith NaHCO₃ (aq) and extracted with DCM (3×30 mL), dried andconcentrated to afford3-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-6,7,8,9-tetrahydro-5H-cyclohepta[c]pyridin-9-amineas yellow solid (170 mg, Y: 92%, used for next step without furtherpurification). ESI-MS (M+H)⁺: 336.2.

15. Synthesis of5-(tert-butyl)-N-(3-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-6,7,8,9-tetrahydro-5H-cyclohepta[c]pyridin-9-yl)-1,3,4-oxadiazole-2-carboxamide(I-IM_29)

To a solution of3-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-6,7,8,9-tetrahydro-5H-cyclohepta[c]pyridin-9-amine(80 mg, 0.24 mmol) and triethylamine (49 mg, 0.48 mmol) in DCM (5 mL)were added HATU (182 mg, 0.48 mmol) and potassium5-(tert-butyl)-1,3,4-oxadiazole-2-carboxylate (75 mg, 0.36 mmol). Themixture was stirred at rt for 3 h. Then water (30 mL) was added and themixture was extracted with DCM (2×50 mL). The combined organics weredried and concentrated. The crude product was purified by silica gelcolumn chromatograph (DCM/MeOH=10:1) to give5-(tert-butyl)-N-(3-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-6,7,8,9-tetrahydro-5H-cyclohepta[c]pyridin-9-yl)-1,3,4-oxadiazole-2-carboxamideas a yellow solid (60 mg, yield: 51%). ESI-MS (M+H)⁺: 487.9. ¹H NMR (400MHz, CD₃OD) δ: 8.52 (s, 1H), 8.49 (d, J=5.2 Hz, 1H), 8.22 (s, 1H), 7.97(s, 1H), 7.66 (s, 1H), 7.54 (d, J=5.2 Hz, 1H), 5.47-5.45 (m, 1H), 3.90(s, 3H), 3.08-3.06 (m, 2H), 2.13-1.98 (m, 5H), 1.51-1.49 (m, 10H).

Example 41:(R)-5-(tert-butyl)-N-(3-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-6,7,8,9-tetrahydro-5H-cyclohepta[c]pyridin-9-yl)-1,3,4-oxadiazole-2-carboxamide(compound 41)

5-(tert-butyl)-N-(3-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-6,7,8,9-tetrahydro-5H-cyclohepta[c]pyridin-9-yl)-1,3,4-oxadiazole-2-carboxamide(216 mg, 0.44 mmol) was subjected to chiral SFC separation (CHIRALPAKAS-H 30×250 mm, 5 um; Co-solvent: 20% Methanol+0.1% DEA in CO₂ (flowrate: 100 g/min); System backpressure: 120 bar) to afford(R)-5-(tert-butyl)-N-(3-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-6,7,8,9-tetrahydro-5H-cyclohepta[c]pyridin-9-yl)-1,3,4-oxadiazole-2-carboxamide(93 mg, yield: 43%) as a white solid. ESI-MS (M+H)⁺: 488.1. ¹H NMR (400MHz, CD₃OD) δ: ppm 8.52 (s, 1H), 8.49 (d, J=5.1 Hz, 1H), 8.22 (s, 1H),7.97 (s, 1H), 7.65 (s, 1H), 7.55 (d, J=5.0 Hz, 1H), 5.46 (br d, J=9.5Hz, 1H), 3.90 (s, 3H), 3.07 (br t, J=4.4 Hz, 2H), 2.12 (br d, J=8.8 Hz,2H), 1.91-2.05 (m, 3H), 1.44-1.57 (m, 10H).

Example 42:(R)-5-(tert-butyl)-N-(3-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-6,7,8,9-tetrahydro-5H-cyclohepta[c]pyridin-9-yl)-1,2,4-oxadiazole-3-carboxamide(compound 42a) &(S)-5-(tert-butyl)-N-(3-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-6,7,8,9-tetrahydro-5H-cyclohepta[c]pyridin-9-yl)-1,2,4-oxadiazole-3-carboxamide(compound 42b)

1. Synthesis of5-(tert-butyl)-N-(3-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-6,7,8,9-tetrahydro-5H-cyclohepta[c]pyridin-9-yl)-1,2,4-oxadiazole-3-carboxamide

Synthesis of5-(tert-butyl)-N-(3-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-6,7,8,9-tetrahydro-5H-cyclohepta[c]pyridin-9-yl)-1,2,4-oxadiazole-3-carboxamidewas similar to that of5-(tert-butyl)-N-(3-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-6,7,8,9-tetrahydro-5H-cyclohepta[c]pyridin-9-yl)-1,3,4-oxadiazole-2-carboxamide(Example 40, Step 15). The filtrate was purified by silica gel columnchromatograph (DCM/MeOH=10:1) to give5-(tert-butyl)-N-(3-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-6,7,8,9-tetrahydro-5H-cyclohepta[c]pyridin-9-yl)-1,2,4-oxadiazole-3-carboxamideas a yellow solid (55 mg, yield: 47%). ESI-MS (M+H)⁺: 487.9. ¹H NMR (400MHz, CD₃OD) δ: 8.50 (s, 1H), 8.49 (d, J=5.6 Hz, 1H), 8.21 (s, 1H), 7.97(s, 1H), 7.66 (s, 1H), 7.54 (d, J=5.2 Hz, 1H), 5.49-5.47 (m, 1H), 3.90(s, 3H), 3.08-3.06 (m, 2H), 2.12-1.97 (m, 5H), 1.52-1.50 (m, 10H).

2. Synthesis of(R)-5-(tert-butyl)-N-(3-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-6,7,8,9-tetrahydro-5H-cyclohepta[c]pyridin-9-yl)-1,2,4-oxadiazole-3-carboxamide(I-IM_31) &(S)-5-(tert-butyl)-N-(3-(2-((1-methyl-H-pyrazol-4-yl)amino)pyrimidin-4-yl)-6,7,8,9-tetrahydro-5H-cyclohepta[c]pyridin-9-yl)-1,2,4-oxadiazole-3-carboxamide(compound 42)

5-(tert-butyl)-N-(3-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-6,7,8,9-tetrahydro-5H-cyclohepta[c]pyridin-9-yl)-1,2,4-oxadiazole-3-carboxamide(40 mg, 0.08 mmol) was subjected to chiral SFC separation (CHIRALPAKAS-H 30×250 mm, 5 um; Co-solvent: 30% Methanol+0.1% DEA in CO2 (flowrate: 100 g/min); System backpressure: 120 bar) to afford(R)-5-(tert-butyl)-N-(3-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-6,7,8,9-tetrahydro-5H-cyclohepta[c]pyridin-9-yl)-1,2,4-oxadiazole-3-carboxamide(11 mg, yield: 27%) δ:(S)-5-(tert-butyl)-N-(3-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-6,7,8,9-tetrahydro-H-cyclohepta[c]pyridin-9-yl)-1,2,4-oxadiazole-3-carboxamide(10 mg, 26%) as white solids.

(R): ESI-MS (M+H)⁺: 488.1. ¹H NMR (400 MHz, CD₃OD) δ: 8.51 (s, 1H), 8.49(s, 1H), 8.22 (s, 1H), 7.97 (s, 1H), 7.65 (s, 1H), 7.55 (d, J=5.1 Hz,1H), 5.48 (br d, J=9.3 Hz, 1H), 3.90 (s, 3H), 3.01-3.11 (m, 2H),1.90-2.14 (m, 5H), 1.50-1.53 (m, 9H).

(S): ESI-MS (M+H)⁺: 488.1. ¹H NMR (400 MHz, CD₃OD) δ: 8.50-8.51 (m, 1H),8.48 (s, 1H), 8.21 (s, 1H), 7.96 (s, 1H), 7.65 (s, 1H), 7.53-7.56 (m,1H), 5.47 (br d, J=9.5 Hz, 1H), 3.89 (s, 3H), 3.02-3.13 (m, 2H),1.91-2.16 (m, 5H), 1.50-1.52 (m, 10H).

Example 43.1-(tert-butyl)-N-(3-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyridin-4-yl)-6,7,8,9-tetrahydro-5H-cyclohepta[c]pyridin-9-yl)-1H-1,2,3-triazole-4-carboxamide(compound 43)

1. Synthesis of tert-butyl(3-(2-chloropyridin-4-yl)-6,7,8,9-tetrahydro-5H-cyclohepta[c]pyridin-9-yl)carbamate

Synthesis of tert-butyl(3-(2-chloropyridin-4-yl)-6,7,8,9-tetrahydro-5H-cyclohepta[c]pyridin-9-yl)carbamatewas similar to that of tert-butyl1-(5-(tert-butyl)-1,2,4-oxadiazole-3-carboxamido)-7-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-4,5-dihydro-1H-benzo[d]azepine-3(2H)-carboxylate(Example 1, Step 12). The crude product was purified by silica gelchromatography (petroleum ether/EtOAc=3:1) to give tert-butyl(3-(2-chloropyridin-4-yl)-6,7,8,9-tetrahydro-5H-cyclohepta[c]pyridin-9-yl)carbamateas a yellow solid (170 mg, yield: 42%). ESI-MS (M+H)⁺: 374.2.

2. Synthesis of tert-butyl(3-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyridin-4-yl)-6,7,8,9-tetrahydro-5H-cyclohepta[c]pyridin-9-yl)carbamate

Synthesis of tert-butyl(3-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyridin-4-yl)-6,7,8,9-tetrahydro-5H-cyclohepta[c]pyridin-9-yl)carbamatewas similar to that of tert-butyl(R)-(2-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyridin-4-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl)carbamate(Example 35, Step 2). The crude product was purified by silica gelcolumn chromatograph (PE/EtOAc=1:1) to give tert-butyl(3-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyridin-4-yl)-6,7,8,9-tetrahydro-5H-cyclohepta[c]pyridin-9-yl)carbamateas a yellow solid (140 mg, Y: 71%). ESI-MS (M+H)⁺: 435.2.

3. Synthesis of3-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyridin-4-yl)-6,7,8,9-tetrahydro-5H-cyclohepta[c]pyridin-9-amine

Synthesis of3-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyridin-4-yl)-6,7,8,9-tetrahydro-5H-cyclohepta[c]pyridin-9-aminewas similar to that of5-(tert-butyl)-N-(7-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-1-yl)-1,2,4-oxadiazole-3-carboxamide(Example 1, Step 13). The crude product3-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyridin-4-yl)-6,7,8,9-tetrahydro-5H-cyclohepta[c]pyridin-9-aminewas obtained as yellow solid (100 mg, yield: 94%). ESI-MS (M+H)⁺: 335.2.

4. Synthesis of1-(tert-butyl)-N-(3-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyridin-4-yl)-6,7,8,9-tetrahydro-5H-cyclohepta[c]pyridin-9-yl)-1H-1,2,3-triazole-4-carboxamide

Synthesis of1-(tert-butyl)-N-(3-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyridin-4-yl)-6,7,8,9-tetrahydro-5H-cyclohepta[c]pyridin-9-yl)-1H-1,2,3-triazole-4-carboxamidewas similar to that of5-(tert-butyl)-N-(3-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-6,7,8,9-tetrahydro-5H-cyclohepta[c]pyridin-9-yl)-1,3,4-oxadiazole-2-carboxamidein Example 40, Step 15. The crude product was purified by silica gelchromatography (DCM/MeOH=15:1) to give1-(tert-butyl)-N-(3-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyridin-4-yl)-6,7,8,9-tetrahydro-5H-cyclohepta[c]pyridin-9-yl)-1H-1,2,3-triazole-4-carboxamideas a yellow solid (46 mg, yield: 32%). ESI-MS (M+H)⁺: 486.3. ¹H NMR (400MHz, CD₃OD) δ: 8.53-8.49 (m, 2H), 8.16 (d, J=5.2 Hz, 1H), 7.92 (s, 1H),7.69 (s, 1H), 7.51 (s, 1H), 7.20-7.17 (m, 2H), 5.45-5.43 (m, 1H), 3.89(s, 3H), 3.08-3.06 (m, 2H), 2.14-2.00 (m, 5H), 1.74 (s, 9H), 1.59-1.50(m, 1H).

Examples 44-154

The following compounds were synthesized according to procedures similarto those described in Examples 1-43.

Compd No. Chemical Name Structure ¹H-NMR and MS  44(S)-5-(tert-butyl)-N-(7- (2-((1-methyl-1H- pyrazol-4-yl)amino)pyrimidin-4- yl)-2,3,4,5-tetrahydro- 1H-benzo[d]azepin- 1-yl)-1,2,4-oxadiazole-3- carboxamide

LCMS: Rt 0.89 min, m/z 488.00. ¹H NMR (400 MHz, METHANOL-d₄) δ: 8.38 (d,J = 5.27 Hz, 1H), 7.83- 8.04 (m, 3H), 7.64 (s, 1H), 7.47 (d, J = 7.97Hz, 1H), 7.19 (s, 1H), 5.34 (d, J = 6.46 Hz, 1H), 3.89 (s, 3H), 2.81-3.28 (m, 6H), 1.43-1.54 (m, 9H).  45 (R)-5-(tert-butyl)-N-(7-(2-((1-methyl-1H- pyrazol-4- yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro- 1H-benzo[d]azepin- 1-yl)- 1,2,4-oxadiazole-3-carboxamide

LCMS: Rt = 0.89 min, m/z 488.00. ¹H NMR (400 MHz, METHANOL-d₄) δ:8.32-8.46 (m, 1H), 7.89-8.05 (m, 3H), 7.64 (s, 1H), 7.48 (d, J = 7.97Hz, 1H), 7.19 (d, J = 5.33 Hz, 1H), 5.34 (d, J = 6.46 Hz, 1H), 3.89 (s,3H), 2.91- 3.28 (m, 6H), 1.45-1.55 (m, 9H).  46 5-(tert-butyl)-N-(3-(2-hydroxyethyl)-7-(2-((1- methyl-1H-pyrazol-4- yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro- 1H-benzo[d]azepin- 1-yl)- 1,3,4-oxadiazole-2-carboxamide

¹H NMR (400 MHz, CD₃OD) δ: 8.28-8.26 (m, 1H), 7.85-7.76 (m, 3H), 7.52(s, 1H), 7.40-7.37 (m, 1H), 7.08-7.05 (m, 1H), 5.15-5.12 (m, 1H), 3.77(s, 3H), 3.65-3.62 (m, 2H), 3.14-3.12 (m, 2H), 2.94-2.91 (m, 2H),2.74-2.65 (m, 3H), 2.61-2.57 (m, 1H), 1.34 (s, 9H). ESI-MS (M + H)⁺:532.3.  47 5-(tert-butyl)-N-(7-(2-((1- methyl-1H-pyrazol-4-yl)amino)pyrimidin-4- yl)-3-(methylsulfonyl)- 2,3,4,5-tetrahydro-1H-benzo[d]azepin-1-yl)- 1,3,4-oxadiazole-2- carboxamide

¹H NMR (400 MHz, CD₃OD) δ: 8.41 (d, J = 5.6 Hz, 1H), 7.99- 7.93 (m, 3H),7.65 (s, 1H), 7.56 (d, J = 7.6 Hz, 1H), 7.16 (d, J = 5.2 Hz, 1H),5.47-5.45 (m, 1H), 4.00-3.95 (m, 1H), 3.90 (s, 3H), 3.82-3.78 (m, 1H),3.65-3.61 (m, 1H), 3.44-3.37 (m, 2H), 3.22-3.17 (m, 1H), 2.90 (s, 3H),1.47 (s, 9H). ESI-MS (M + H)⁺: 566.2.  48 5-(tert-butyl)-N-(7-(2-((1-methyl-1H-pyrazol-4- yl)amino)pyrimidin-4- yl)-3-(oxetan-3-yl)-2,3,4,5-tetrahydro-1H- benzo[d]azepin-1-yl)- 1,3,4-oxadiazole-2-carboxamide

¹H NMR (400 MHz, CD₃OD) δ: 8.29 (d, J = 5.2 Hz, 1H), 7.85-7.80 (m, 3H),7.52 (s, 1H), 7.41 (d, J = 8.0 Hz, 1H), 7.08 (d, J = 4.8 Hz, 1H),5.16-5.15 (m, 1H), 4.62-4.58 (m, 3H), 4.55-4.51 (m, 1H), 3.78 (s, 3H),3.70-3.66 (m, 1H), 3.20-3.15 (m, 1H), 2.98-2.93 (m, 1H), 2.88-2.83 (m,1H), 2.70-2.66 (m, 1H), 2.47- 2.44 (m, 1H), 2.35-2.29 (m, 1H), 1.35 (s,9H). ESI-MS (M + H)⁺: 544.3.  49 5-(tert-butyl)-N-(7-(2-((1-methyl-1H-pyrazol-4- yl)amino)pyrimidin-4- yl)-3-(tetrahydrofuran-3-yl)-2,3,4,5-tetrahydro- 1H-benzo[d]azepin-1-yl)- 1,3,4-oxadiazole-2-carboxamide

¹H NMR (400 MHz, CD₃OD) δ: 8.39 (d, J = 5.6 Hz, 1H), 7.96 (s, 1H), 7.94(dd, J = 8.0, 2.0 Hz, 1H), 7.89 (s, 1H), 7.64 (s, 1H), 7.51 (d, J = 8.0Hz, 1H), 7.18 (d, J = 5.2 Hz, 1H), 5.24-5.22 (m, 1H), 4.01-3.96 (m, 1H),3.89 (s, 3H), 3.87-3.83 (m, 1H), 3.80-3.70 (m, 2H), 3.53-3.49 (m, 1H),3.29-3.20 (m, 2H), 3.15-2.97 (m, 2H), 2.82-2.62 (m, 2H), 2.15- 2.10 (m,1H), 1.98-1.91 (m, 1H), 1.46 (s, 9H). ESI-MS (M + H)⁺: 558.3.  505-(tert-butyl)-N-(3-(2- hydroxy-2- methylpropyl)-7-(2-((1-methyl-1H-pyrazol-4- yl)amino)pyrimidin-4- yl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-1-yl)- 1,3,4-oxadiazole-2- carboxamide

¹H NMR (400 MHz, CD₃OD) δ: 8.40 (d, J = 4.8 Hz, 1H), 7.97-7.89 (m, 3H),7.64 (s, 1H), 7.51 (d, J = 8.0, 2.0 Hz, 1H), 7.20-7.19 (m, 1H),5.22-5.20 (m, 1H), 3.89 (s, 3H), 3.29-3.21 (m, 3H), 3.05-3.00 (m, 1H),2.93-2.90 (m, 1H), 2.77-2.72 (m, 1H), 2.60 (s, 2H), 1.46 (s, 9H),1.32-1.31 (m, 6H). ESI-MS (M + H)⁺: 560.3.  51 1-(tert-butyl)-N-(7-(2-((1-methyl-1H-pyrazol- 4-yl)amino)pyrimidin- 4-yl)-2,3,4,5-tetrahydro-1H- benzo[d]azepin-1-yl)- 1H-1,2,3-triazole-4- carboxamide

¹H NMR (400 MHz, CD₃OD) δ: 8.48 (s, 1H), 8.40 (d, J = 5.6 Hz, 1H),7.98-7.93 (m, 3H), 7.65 (br, 1H), 7.50 (d, J = 7.6 Hz, 1H), 7.21 (d, J =5.2 Hz, 1H), 5.35-5.34 (m, 1H), 3.90 (s, 3H), 3.28-2.99 (m, 6H), 1.73(s, 9H). ESI-MS (M + H)⁺: 487.2.  52 1-(tert-butyl)-N-(3-methyl-7-(2-((1- methyl-1H-pyrazol-4- yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro- 1H-benzo[d]azepin-1- yl)-1H-1,2,3-triazole-4-carboxamide

¹H NMR (400 MHz, CD₃OD) δ: 8.45 (s, 1H), 8.41 (d, J = 5.2 Hz, 1H),7.98-7.92 (m, 3H), 7.65 (s, 1H), 7.52 (d, J = 8.0 Hz, 1H), 7.21 (d, J =5.2 Hz, 1H), 5.33-5.31 (m, 1H), 3.90 (s, 3H), 3.31-3.26 (m, 1H),3.11-3.05 (m, 2H), 2.92-2.59 (m, 3H), 2.51 (s, 3H), 1.72 (s, 9H). ESI-MS(M + H)⁺: 501.3.  53 1-(tert-butyl)-N-(3-(2- hydroxyethyl)-7-(2-((1-methyl-1H-pyrazol-4- yl)amino)pyrimidin-4- yl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-1- yl)-1H-1,2,3-triazole-4- carboxamide

¹H NMR (400 MHz, CD₃OD) δ: 8.44 (s, 1H), 8.41 (d, J = 5.2 Hz, 1H),7.98-7.91 (m, 3H), 7.65 (s, 1H), 7.54 (d, J = 7.6 Hz, 1H), 7.21 (d, J =5.2 Hz, 1H), 5.21-5.25 (m, 1H), 3.90 (s, 3H), 3.79-3.76 (m, 2H),3.19-3.02 (m, 4H), 2.86-2.64 (m, 4H), 1.71 (s, 9H). ESI-MS (M + H)⁺:531.3.  54 5-(tert-butyl)-N-(8-(2-((1- methyl-1H-pyrazol-4-yl)amino)pyrimidin-4- yl)-2-(2,2,2- trifluoroethyl)-2,3,4,5-tetrahydro-1H- benzo[c]azepin-5-yl)- 1,2,4-oxadiazole-3- carboxamide

ESI-MS (M + H)⁺: 570.2. ¹H NMR (400 MHz, CD₃OD) δ: 8.31 (d, J = 4.8 Hz,1H), 7.93-7.88 (m, 3H), 7.50 (s, 1H), 7.37 (d, J = 8.4 Hz, 1H), 7.12 (d,J = 4.8 Hz, 1H), 5.51 (d, J = 10.0 Hz, 1H), 4.26-4.22 (m, 1H), 4.02-3.98(m, 1H), 3.48 (s, 3H), 3.30-3.27 (m, 2H), 3.05-2.98 (m, 2H), 2.13-2.08(m, 1H), 1.85-1.82 (m, 1H), 1.41 (s, 9H).  55 5-(tert-butyl)-N-(2-(2-(dimethylamino)acetyl)- 8-(2-((1-methyl-1H- pyrazol-4-yl)amino)pyrimidin-4- yl)-2,3,4,5-tetrahydro- 1H-benzo[c]azepin-5-yl)-1,2,4-oxadiazole-3- carboxamide

ESI-MS (M + H)⁺: 573.3. ¹H NMR (400 MHz, CD₃OD) δ: 8.33-8.29 (m, 1H),8.10 (s, 1H), 8.02-7.86 (m, 2H), 7.56-7.34 (m, 2H), 7.15-7.12 (m, 1H),5.61-5.50 (m, 1H), 5.03-4.94 (m, 2H), 4.77-4.36 (m, 1H), 4.16- 4.13 (m,1H), 4.04-3.99 (m, 3H), 3.83-3.35 (m, 2H), 3.10-3.05 (m, 2H), 2.17-2.12(m, 6H), 1.42 (s, 9H).  56 N-(2-(2-hydroxyethyl)- 8-(2-((1-methyl-1H-pyrazol-4- yl)amino)pyrimidin-4- yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5- yl)-5-(1,1,1-trifluoro-2- methylpropan-2-yl)-1,3,4-oxadiazole-2- carboxamide

ESI-MS (M + H)⁺: 586.3. ¹H NMR (400 MHz, CD₃OD) δ: 8.43 (d, J = 5.2 Hz,1H), 8.05 (s, 1H), 8.03-8.00 (m, 2H), 7.65 (s, 1H), 7.49 (d, J = 7.6 Hz,1H), 7.24 (d, J = 5.2 Hz, 1H), 5.59-5.57 (m, 1H), 4.64 (br, 1H),4.17-4.15 (m, 2H), 3.91 (s, 3H), 3.75 (t, J = 6.0 Hz, 2H), 3.26-3.16 (m,1H), 2.72-2.61 (m, 2H), 2.34- 2.25 (m, 1H), 2.02-1.97 (m, 1H), 1.76 (s,6H).  57 N-(2-methyl-8-(2-((1- methyl-1H-pyrazol-4-yl)amino)pyrimidin-4- yl)-2,3,4,5-tetrahydro- 1H-benzo[c]azepin-5-yl)-5-(1,1,1-trifluoro-2- methylpropan-2-yl)- 1,3,4-oxadiazole-2-carboxamide

ESI-MS (M + H)⁺: 556.2. ¹H NMR (400 MHz, CDCl₃) δ: 8.52 (br, 1H), 8.42(d, J = 5.2 Hz, 1H), 7.87 (s, 1H), 7.85-7.81 (m, 2H), 7.55 (s, 1H), 7.47(d, J = 8.0 Hz, 1H), 7.05 (d, J = 5.2 Hz, 1H), 6.91 (s, 1H), 5.61-5.56(m, 1H), 3.94-3.92 (m, 5H), 3.14- 3.07 (m, 1H), 2.85-2.80 (m, 1H), 2.52(s, 3H), 2.36-2.28 (m, 1H), 2.11-2.03 (m, 1H), 1.71 (s, 6H).  58(R)-5-(1,1-difluoro-2- methylpropan-2-yl)- N-(8- (2-((1-methyl-1H-pyrazol-4- yl)amino)pyrimidin-4- yl)-2-(oxetan-3-yl)-2,3,4,5-tetrahydro-1H- benzo[c]azepin-5-yl)- 1,3,4-oxadiazole-2-carboxamide

ESI-MS (M + H)⁺: 580.2. ¹H NMR (400 MHz, CD₃OD) δ: 8.42 (d, J = 5.2 Hz,1H), 8.04 (d, J = 8.0 Hz, 1H), 7.99-7.98 (m, 2H), 7.64 (s, 1H), 7.48 (d,J = 8.0 Hz, 1H), 7.23 (d, J = 5.2 Hz, 1H), 6.15 (t, J = 55.6 Hz, 1H),5.60-5.56 (m, 1H), 4.78-4.75 (m, 1H), 4.70-4.66 (m, 3H), 3.98- 3.94 (m,1H), 3.90 (s, 3H), 3.88-3.79 (m, 2H), 3.09-3.06 (m, 1H), 2.93- 2.87 (m,1H), 2.30-2.20 (m, 1H), 2.07-2.04 (m, 1H), 1.60 (s, 6H).  595-(1,1-difluoro-2- methylpropan-2-yl)- N-(2-((S)-2- hydroxypropyl)-8-(2-((1-methyl-1H- pyrazol-4- yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro- 1H-benzo[c]azepin- 5-yl)- 1,3,4-oxadiazole-2-carboxamide

ESI-MS (M + H)⁺: 582.3. ¹H NMR (400 MHz, CD₃OD) δ: 8.42 (d, J = 5.2 Hz,1H), 8.03-8.00 (m, 3H), 7.64 (s, 1H), 7.48-7.46 (m, 1H), 7.23 (d, J =5.2 Hz, 1H), 6.15 (t, J = 55.6 Hz, 1H), 5.57 (d, J = 9.6 Hz, 1H), 4.23-4.19 (m, 1H), 4.13-4.06 (m, 1H), 4.00-3.96 (m, 1H), 3.91 (s, 3H),3.26-3.20 (m, 2H), 2.44 (d, J = 6.0 Hz, 2H), 2.31-2.25 (m, 1H),1.99-1.95 (m, 1H), 1.60 (s, 6H), 1.16 (d, J = 6.0 Hz, 3H).  605-(1-fluoro-2- methylpropan-2-yl)- N-(8- (2-((1-methyl-1H- pyrazol-4-yl)amino)pyrimidin-4- yl)-2-(oxetan-3-yl)- 2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)- 1,3,4-oxadiazole-2- carboxamide

ESI-MS (M + H)⁺: 562.3. ¹H NMR (400 MHz, CD₃OD) δ: 8.29 (d, J = 5.6 Hz,1H), 8.21 (s, 1H), 7.91-7.89 (m, 1H), 7.86-7.83 (m, 2H), 7.35 (d, J =8.0 Hz, 1H), 7.09 (d, J = 5.6 Hz, 1H), 5.46 (d, J = 9.6 Hz, 1H), 4.75-4.57 (m, 1H), 4.56-4.55 (m, 4H), 4.43 (s, 1H), 3.85-3.66 (m, 6H),2.96-2.92 (m, 1H), 1.94-1.91 (m, 1H), 1.41 (d, J = 2.0 Hz, 6H), 1.19 (m,2H).  61 5-(1-fluoro-2- methylpropan-2-yl)-N-(2-((S)-2-hydroxypropyl)-8- (2-((1-methyl-1H- pyrazol-4-yl)amino)pyrimidin-4- yl)-2,3,4,5-tetrahydro- 1H-benzo[c]azepin-5-yl)-1,3,4-oxadiazole-2- carboxamide

ESI-MS (M + H)⁺: 564.3. ¹H NMR (400 MHz, MeOD) δ: 8.31-8.29 (m, 1H),7.89-7.88 (m, 3H), 7.55 (s, 1H), 7.38-7.36 (m, 1H), 7.11-7.10 (m, 1H),5.48-5.46 (m, 1H), 4.53 (d, J = 47.2 Hz, 2H), 4.11-3.86 (m, 3H), 3.81(s, 3H), 3.21-3.14 (m, 2H), 2.35-2.17 (m, 3H), 1.89-1.87 (m, 1H), 1.44(s, 6H), 1.07-1.03 (m, 3H).  62 5-cyclobutyl-N-(2- methyl-8-(2-((1-methyl-1H-pyrazol-4- yl)amino)pyrimidin-4- yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5- yl)-1,3,4-oxadiazole-2- carboxamide

ESI-MS (M + H)⁺: 500.3. ¹H NMR (400 MHz, CD₃OD) δ: 8.31-8.28 (m, 1H),7.92-7.86 (m, 3H), 7.52 (s, 1H), 7.35-7.33 (m, 1H), 7.12-7.08 (m, 1H),5.43 (d, J = 10.0 Hz, 1H), 4.00- 3.98 (m, 1H), 3.82-3.79 (m, 2H), 3.77(s, 3H), 3.08-2.95 (m, 2H), 2.45-2.38 (m, 4H), 2.28 (s, 3H), 2.15-1.89(m, 4H).  63 5-(2-cyanopropan-2- yl)-N-(2-methyl-8-(2-((1-methyl-1H-pyrazol- 4-yl)amino)pyrimidin- 4-yl)-2,3,4,5-tetrahydro-1H- benzo[c]azepin-5-yl)- 1,3,4-oxadiazole-2- carboxamide

ESI-MS (M + H)⁺: 513.6. ¹H NMR (400 MHz, CDCl₃) δ: 8.59-8.58 (m, 1H),8.41 (d, J = 5.2 Hz, 1H), 7.85- 7.81 (m, 3H), 7.53 (s, 1H), 7.45 (d, J =7.6 Hz, 1H), 7.04 (d, J = 5.2 Hz, 1H), 5.58 (t, J = 8.0 Hz, 1H), 3.93-3.92 (m, 1H), 3.90 (s, 3H), 3.13-3.06 (m, 1H), 2.86-2.80 (m, 1H), 2.51(s, 3H), 2.35-2.28 (m, 1H), 2.10-2.03 (m, 2H), 1.91 (s, 6H).  645-(2-cyanopropan-2-yl)- N-(2-(2-hydroxyethyl)-8- (2-((1-methyl-1H-pyrazol-4- yl)amino)pyrimidin-4- yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)- 1,3,4-oxadiazole-2- carboxamide

ESI-MS (M + H)⁺: 543.6. ¹H NMR (400 MHz, CD₃OD) δ: 8.40 (d, J = 5.2 Hz,1H), 8.01-7.98 (m, 3H), 7.64 (s, 1H), 7.47 (d, J = 8.0 Hz, 1H), 7.20 (d,J = 5.2 Hz, 1H), 5.57 (d, J = 9.6 Hz, 1H), 4.20-4.11 (m, 2H), 3.90 (s,3H), 3.75-3.72 (m, 2H), 3.28-3.20 (m, 2H), 2.68-2.63 (m, 2H), 2.31- 2.27(m, 1H), 2.01-1.97 (m, 1H), 1.94 (s, 6H).  65 1-isopropyl-N-(8-(2-((1-methyl-1H-pyrazol- 4-yl)amino)pyrimidin- 4-yl)-2-(oxetan-3-yl)-2,3,4,5-tetrahydro-1H- benzo[c]azepin-5-yl)- 1H-1,2,3-triazole-4-carboxamide

ESI-MS (M + H)⁺: 529.2. ¹H NMR (400 MHz, DMSO-d₆) δ: 9.49 (s, 1H), 9.05(d, J = 8.0 Hz, 1H), 8.74 (s, 1H), 8.46 (d, J = 5.2 Hz, 1H), 8.03-7.81(m, 3H), 7.54 (s, 1H), 7.37 (d, J = 8.0 Hz, 1H), 7.25 (d, J = 5.2 Hz,1H), 5.44 (t, J = 9.6 Hz, 1H), 5.00-4.80 (m, 1H), 4.59 (t, J = 6.4 Hz,1H), 4.56-4.41 (m, 3H), 3.93- 3.59 (m, 6H), 2.98-2.70 (m, 2H), 2.19-2.03(m, 1H), 1.90-1.77 (m, 1H), 1.54 (d, J = 6.8 Hz, 6H).  661-cyclobutyl-N-(8-(2- ((1-methyl-1H-pyrazol- 4-yl)amino)pyrimidin-4-yl)-2-(oxetan-3-yl)- 2,3,4,5-tetrahydro-1H- benzo[c]azepin-5-yl)-1H-1,2,3-triazole-4- carboxamide

ESI-MS (M + H)⁺: 540.7. ¹H NMR (400 MHz, DMSO-d₆) δ: 9.49 (s, 1H), 9.07(d, J = 8.4 Hz, 1H), 8.81 (s, 1H), 8.47 (d, J = 5.2 Hz, 1H), 7.97-7.94(m, 2H), 7.90 (s, 1H), 7.53 (s, 1H), 7.37 (d, J = 8.0 Hz, 1H), 7.26 (d,J = 5.2 Hz, 1H), 5.44 (t, J = 9.6 Hz, 1H), 5.25-5.16 (m, 1H), 4.59 (t, J= 6.4 Hz, 1H), 4.54-4.47 (m, 3H), 3.88-3.62 (m, 2H), 3.68 (s, 3H),2.93-2.90 (m, 1H), 2.81-2.76 (m, 1H), 2.74-2.72 (m, 1H), 2.60-2.48 (m,4H), 2.14-2.06 (m, 1H), 1.92- 1.83 (m, 3H).  675-(tert-butyl)-N-(8-(2-((1- methyl-1H-pyrazol-4- yl)amino)pyrimidin-4-yl)-2-(oxetan-3-yl)- 2,3,4,5-tetrahydro-1H- benzo[c]azepin-5-yl)-1,3,4-thiadiazole-2- carboxamide

ESI-MS (M + H)⁺: 560.0. ¹H NMR (400 MHz, CDCl₃) δ: 8.42 (d, J = 5.2 Hz,1H), 8.33 (d, J = 8.4 Hz, 1H), 7.87 (s, 1H), 7.86 (dd, J = 8.0 Hz, 1.6Hz, 1H), 7.77 (d, J = 1.6 Hz, 1H), 7.53 (s, 1H), 7.49 (d, J = 8.0 Hz,1H), 7.04 (d, J = 5.2 Hz, 1H), 6.95 (s, 1H), 5.62-5.58 (m, 1H),4.77-4.68 (m, 4H), 3.92-3.86 (m, 6H), 3.04-2.97 (m, 1H), 2.81-2.75 (m,1H), 2.32-2.26 (m, 1H), 2.13- 2.06 (m, 1H), 1.51 (s, 9H).  683-(tert-butyl)-N-(2-(3- hydroxycyclobutyl)-8-(2-((1-methyl-1H-pyrazol-4- yl)amino)pyrimidin-4- yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)- 1,2,4-oxadiazole-5- carboxamide

ESI-MS (M + H)⁺: 558.3. ¹H NMR (400 MHz, CDCl₃) δ: 8.61 (br, 1H), 8.43(d, J = 4.8 Hz, 1H), 7.85-7.82 (m, 3H), 7.55 (s, 1H), 7.49 (d, J = 7.6Hz, 1H), 7.05 (d, J = 4.2 Hz, 1H), 7.02 (s, 1H), 5.61 (t, J = 8.0 Hz,1H), 4.07-3.73 (m, 6H), 3.15-3.06 (m, 1H), 2.73-2.49 (m, 3H), 2.37- 2.30(m, 1H), 2.12-1.85 (m, 4H), 1.39 (s, 9H).  69 1-(tert-butyl)-N-(8-(2-((1-methyl-1H-pyrazol- 4-yl)amino)pyrimidin- 4-yl)-2,3,4,5-tetrahydro-1H- benzo[c]azepin-5-yl)- 1H-1,2,3-triazole-4- carboxamide

ESI-MS (M + H)⁺: 487.2. ¹H NMR (400 MHz, CDCl₃) δ: 8.40 (d, J = 5.2 Hz,1H), 8.19 (s, 1H), 7.98 (d, J = 8.8 Hz, 1H), 7.89 (s, 1H), 7.84-7.81 (m,2H), 7.51-7.47 (m, 2H), 7.03 (d, J = 5.2 Hz, 1H), 5.63 (t, J = 9.2 Hz,1H), 4.16-4.14 (m, 2H), 3.90 (s, 3H), 3.42-3.32 (m, 2H), 2.10-2.08 (m,2H), 1.71 (s, 9H).  70 1-(tert-butyl)-N-(2-ethyl- 8-(2-((1-methyl-1H-pyrazol-4- yl)amino)pyrimidin-4- yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)- 1H-1,2,3-triazole-4- carboxamide

ESI-MS (M + H)⁺: 514.8. ¹H NMR (400 MHz, CDCl₃) δ: 8.41 (d, J = 5.2 Hz,1H), 8.17 (s, 1H), 7.91 (s, 1H), 7.84-7.24 (m, 2H), 7.53 (s, 1H), 7.48(d, J = 8.8 Hz, 1H), 7.04 (d, J = 5.2 Hz, 2H), 6.95 (s, 1H), 5.61 (t, J= 9.2 Hz, 1H), 4.02 (s, 2H), 3.91 (s, 3H), 3.31-3.22 (m, 1H), 3.02-2.98(m, 1H), 2.66-2.60 (m, 2H), 2.28-2.21 (m, 1H), 2.06-2.02 (m, 1H), 1.67(s, 9H), 1.20 (t, J = 7.2 Hz, 3H).  71 1-(tert-butyl)-N-(8-(2-((1-methyl-1H-pyrazol- 4-yl)amino)pyrimidin- 4-yl)-2-(oxetan-3-yl)-2,3,4,5-tetrahydro-1H- benzo[c]azepin-5-yl)- 1H-1,2,3-triazole-4-carboxamide

ESI-MS (M + H)⁺: 542.7. ¹H NMR (400 MHz, CD₃OD) δ: 8.52 (s, 1H), 8.42(d, J = 5.6 Hz, 1H), 8.02 (d, J = 7.6 Hz, 1H), 7.98-7.97 (m, 2H), 7.64(s, 1H), 7.48 (d, J = 8.0 Hz, 1H), 7.22 (d, J = 4.4 Hz, 1H), 5.60-5.57(m, 1H), 4.76 (t, J = 6.4 Hz, 1H), 4.71-4.69 (m, 3H), 3.99-3.82 (m, 6H),3.10-3.05 (m, 1H), 2.92-2.86 (m, 1H), 2.27-2.18 (m, 1H), 2.07- 2.02 (m,1H), 1.74 (s, 9H).  72 1-(tert-butyl)-N-(2-(3- hydroxycyclobutyl)-8-(2-((1-methyl-1H-pyrazol-4- yl)amino)pyrimidin-4- yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)- 1H-1,2,3-triazole-4- carboxamide

ESI-MS (M + H)⁺: 556.7. ¹H NMR (400 MHz, CDCl₃) δ: 8.41 (d, J = 5.2 Hz,1H), 8.17 (s, 1H), 7.88 (s, 1H), 7.81-7.78 (m, 2H), 7.54 (s, 1H), 7.48(d, J = 8.4 Hz, 1H), 7.04-7.02 (s, 2H), 5.59 (t, J = 8.4 Hz, 1H), 4.03-3.79 (m, 6H), 3.19-3.13 (m, 1H), 2.76-2.63 (m, 4H), 2.31-2.25 (m, 1H),2.15-1.93 (m, 3H), 1.68 (s, 9H).  73 1-(tert-butyl)-N-(8-(2-((1-methyl-1H- pyrazol-4- yl)amino)pyrimidin-4-yl)-2-(tetrahydrofuran-3- yl)-2,3,4,5-tetrahydro- 1H-benzo[c]azepin-5-yl)- 1H-1,2,3-triazole-4- carboxamide

ESI-MS (M + H)⁺: 556.7. ¹H NMR (400 MHz, CD₃OD) δ: 8.47 (s, 1H), 8.38(d, J = 5.2 Hz, 1H), 7.98-7.95 (m, 3H), 7.62 (d, J = 5.2 Hz, 1H), 7.47(d, J = 7.6 Hz, 1H), 7.17 (d, J = 5.2 Hz, 1H), 5.57-5.55 (m, 1H),4.09-3.94 (m, 4H), 3.89 (s, 3H), 3.78-3.70 (m, 2H), 3.28-3.06 (m, 3H),2.32-1.94 (m, 4H), 1.74 (s, 9H).  74 1-(tert-butyl)-N-(8- (2-((1-methyl-1H-pyrazol-4- yl)amino)pyrimidin-4- yl)-2-(tetrahydro-2H-pyran-4-yl)-2,3,4,5- tetrahydro-1H- benzo[c]azepin-5-yl)- 1H-1,2,3-triazole-4- carboxamide

ESI-MS (M + H)⁺: 570.7. ¹H NMR (400 MHz, CDCl₃) δ: 8.41 (d, J = 4.8 Hz,1H), 8.22 (d, J = 10.0 Hz, 1H), 8.16 (s, 1H), 7.88 (s, 1H), 7.83-7.80(m, 2H), 7.50 (s, 1H), 7.48 (d, J = 7.6 Hz, 1H), 7.04 (d, J = 5.2 Hz,1H), 6.93 (s, 1H), 5.65 (t, J = 8.4 Hz, 1H), 4.10-4.05 (m, 4H), 3.91 (s,3H), 3.44-3.37 (m, 2H), 3.19-3.16 (m, 1H), 3.10-3.05 (m, 1H), 2.86-2.81(m, 1H), 2.31-2.26 (m, 1H), 2.10- 2.04 (m, 1H), 1.95-1.70 (m, 4H), 1.69(s, 9H).  75 1-(tert-butyl)-N-(8- (2-((1- methyl-1H-pyrazol-4-yl)amino)pyrimidin-4- yl)-2-(2,2,2- trifluoroethyl)-2,3,4,5-tetrahydro-1H- benzo[c]azepin-5- yl)-1H- 1,2,3-triazole-4- carboxamide

ESI-MS (M + H)⁺: 568.7. ¹H NMR (400 MHz, CDCl₃) δ: 8.42 (d, J = 5.2 Hz,1H), 8.18 (s, 1H), 7.91 (s, 1H), 7.87 (d, J = 7.6 Hz, 1H), 7.83 (s, 1H),7.78 (d, J = 8.8 Hz, 1H), 7.51 (s, 1H), 7.48 (d, J = 8.0 Hz, 1H), 7.05(d, J = 5.2 Hz, 1H), 7.02 (s, 1H), 5.61 (t, J = 8.4 Hz, 1H), 4.33- 4.12(m, 2H), 3.91 (s, 3H), 3.41-3.35 (m, 2H), 3.10-3.03 (m, 2H), 2.22- 2.14(m, 1H), 2.03-1.97 (m, 1H), 1.71 (s, 9H).  76 1-(tert-butyl)-N-(2-(2-hydroxyethyl)-8-(2-((1- methyl-1H-pyrazol-4- yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro- 1H-benzo[c]azepin- 5-yl)- 1H-1,2,3-triazole-4-carboxamide

ESI-MS (M + H)⁺: 531.3. ¹H NMR (400 MHz, CDCl₃) δ: 8.50 (br, 1H), 8.41(d, J = 5.2 Hz, 1H), 8.16 (s, 1H), 7.88 (s, 1H), 7.83-7.80 (m, 2H), 7.54(s, 1H), 7.49 (d, J = 7.6 Hz, 1H), 7.03 (d, J = 5.2 Hz, 1H), 6.91 (s,1H), 5.61 (t, J = 8.8 Hz, 1H), 4.14-4.03 (m, 2H), 3.92 (s, 3H),3.80-3.79 (m, 2H), 3.29-3.26 (m, 1H), 3.99-3.96 (m, 1H), 2.80-2.77 (m,2H), 2.30-2.27 (m, 1H), 2.08- 2.01 (m, 1H), 1.70 (s, 9H).  771-(tert-butyl)-N-(2-((R)- 2-hydroxypropyl)-8-(2-((1-methyl-1H-pyrazol-4- yl)amino)pyrimidin-4- yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)- 1H-1,2,3-triazole-4- carboxamide

ESI-MS (M + H)⁺: 544.3. ¹H NMR (400 MHz, DMSO-d₆) δ: 9.50 (s, 1H), 9.00(d, J = 7.2 Hz, 1H), 8.75 (s, 1H), 8.45 (d, J = 5.2 Hz, 1H), 7.95 (s,3H), 7.53 (s, 1H), 7.36 (d, J = 8.0 Hz, 1H), 7.25 (d, J = 5.2 Hz, 1H),5.46-5.42 (m, 1H), 4.35-3.94 (m, 3H), 3.82-3.76 (m, 4H), 3.31- 3.13 (m,2H), 2.36-2.11 (m, 3H), 1.79-1.73 (m, 1H), 1.65 (s, 9H), 1.03 (t, J =5.2 Hz, 3H).  78 5-(tert-butyl)-N-(2- ((R)-2-hydroxypropyl)-8-(2-((1-methyl-1H- pyrazol-4- yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro- 1H-benzo[c]azepin-5- yl)-1,2,4-oxadiazole-3-carboxamide

ESI-MS (M + H)⁺: 546.3. ¹H NMR (400 MHz, CD₃OD) δ: 8.42 (d, J = 5.2 Hz,1H), 8.03-7.99 (m, 3H), 7.64 (s, 1H), 7.46 (d, J = 7.2 Hz, 1H),7.24-7.22 (m, 1H), 5.61-5.58 (m, 1H), 4.22-3.98 (m, 3H), 3.91 (s, 3H),3.28-3.21 (m, 2H), 2.47-2.26 (m, 3H), 1.97-1.94 (m, 1H), 1.52 (s, 9H),1.16-1.28 (m, 3H).  79 5-(tert-butyl)-N-(2-(2- methoxyethyl)-8-(2-((1-methyl-1H-pyrazol-4- yl)amino)pyrimidin-4- yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)- 1,2,4-oxadiazole-3- carboxamide

ESI-MS (M + H)⁺: 545.7. ¹H NMR (400 MHz, CD₃OD) δ: 8.43 (d, J = 5.2 Hz,1H), 8.05-8.03 (m, 2H), 7.99 (s, 1H), 7.65 (s, 1H), 7.46 (d, J = 8.8 Hz,1H), 7.24 (d, J = 5.6 Hz, 1H), 5.59 (d, J = 10.0 Hz, 1H), 4.22-4.11 (m,2H), 3.90 (s, 3H), 3.61 (t, J = 5.6 Hz, 2H), 3.36 (s, 3H), 3.27-3.15 (m,2H), 2.77-2.69 (m, 2H), 2.31-2.25 (m, 1H), 2.00-1.97 (m, 1H), 1.53 (s,9H).  80 5-(tert-butyl)-N-(8- (2-((1- methyl-1H-pyrazol-4-yl)amino)pyrimidin-4- yl)-2-(tetrahydrofuran-3- yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin- 5-yl)- 1,3,4-oxadiazole-2- carboxamide

ESI-MS (M + H)⁺: 558.3. ¹H NMR (400 MHz, CD₃OD) δ: 8.42 (d, J = 5.2 Hz,1H), 8.04-7.99 (m, 3H), 7.64-7.63 (m, 1H), 7.50 (d, J = 8.0 Hz, 1H),7.24 (d, J = 5.2 Hz, 1H), 5.59 (d, J = 10.0 Hz, 1H), 4.10-3.91 (m, 4H),3.90 (s, 3H), 3.79-3.70 (m, 2H), 3.32-3.12 (m, 3H), 2.30-2.18 (m, 2H),2.05-1.97 (m, 2H), 1.51 (s, 9H).  81 5-(tert-butyl)-N-(2-(3-hydroxycyclobutyl)-8-(2- ((1-methyl-1H-pyrazol-4- yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro- 1H-benzo[c]azepin- 5-yl)- 1,3,4-oxadiazole-2-carboxamide

ESI-MS (M + H)⁺: 558.2. ¹H NMR (400 MHz, CD₃OD) δ: 8.42 (d, J = 5.2 Hz,1H), 8.03-8.01 (m, 3H), 7.63 (s, 1H), 7.47 (d, J = 8.4 Hz, 1H), 7.23 (d,J = 5.2 Hz, 1H), 5.56-5.54 (m, 1H), 3.98-3.87 (m, 6H), 3.25- 3.21 (m,1H), 2.96-2.91 (m, 1H), 2.64-2.18 (m, 4H), 2.02-1.83 (m, 3H), 1.51 (s,9H).  82 (R)-5-(tert-butyl)-N-(2- (3-hydroxycyclobutyl)-8-(2-((1-methyl-1H- pyrazol-4- yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro- 1H-benzo[c]azepin- 5-yl)- 1,3,4-oxadiazole-2-carboxamide

LCMS: Rt 2.9 min, m/z 558.00. ¹H NMR (400 MHz, METHANOL-d₄) δ: 8.41 (d,J = 5.3 Hz, 1H), 8.07-7.94 (m, 3H), 7.65-7.59 (m, 1H), 7.50- 7.43 (m,1H), 7.22 (d, J = 5.3 Hz, 1H), 5.54 (br d, J = 9.5 Hz, 1H), 4.58 (s,1H), 4.07-3.94 (m, 2H), 3.92-3.82 (m, 4H), 3.29-3.18 (m, 1H), 3.04- 2.78(m, 1H), 2.66-2.50 (m, 2H), 2.37-2.10 (m, 1H), 2.10-1.94 (m, 1H),1.88-1.79 (m, 2H), 1.49 (s, 9H), 0.98-0.79 (m, 1H).  835-(tert-butyl)-N-(2-ethyl- 8-(2-((1-methyl-1H- pyrazol-4-yl)amino)pyrimidin-4- yl)-2,3,4,5-tetrahydro- 1H-benzo[c]azepin- 5-yl)-1,3,4-oxadiazole-2- carboxamide

ESI-MS (M + H)⁺: 516.2. ¹H NMR (400 MHz, CD₃OD) δ: 8.41 (d, J = 5.2 Hz,1H), 8.04-7.98 (m, 3H), 7.64 (s, 1H), 7.47 (d, J = 7.6 Hz, 1H), 7.21 (d,J = 5.2 Hz, 1H), 5.56-5.54 (m, 1H), 4.07 (s, 2H), 3.90 (s, 3H),3.30-3.07 (m, 2H), 2.61-2.55 (m, 2H), 2.28-2.00 (m, 2H), 1.51 (s, 9H),1.19 (t, J = 7.2 Hz, 3H).  84 (R)-5-(tert-butyl)-N-(2-ethyl-8-(2-((1-methyl- 1H-pyrazol-4- yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro- 1H-benzo[c]azepin-5- yl)- 1,3,4-oxadiazole-2-carboxamide

LCMS: Rt 2.7 min, m/z 516.10. ¹H NMR (400 MHz, METHANOL-d₄) δ: 8.38 (d,J = 5.3 Hz, 1H), 8.02-7.98 (m, 2H), 7.96 (s, 1H), 7.62 (s, 1H), 7.44 (d,J = 7.8 Hz, 1H), 7.19 (d, J = 5.3 Hz, 1H), 5.53 (br d, J = 9.3 Hz, 1H),4.05 (s, 2H), 3.87 (s, 3H), 3.29- 3.22 (m, 1H), 3.09 (ddd, J = 13.3 Hz,10.4 Hz, 2.9 Hz, 1H), 2.64-2.50 (m, 2H), 2.31-2.17 (m, 1H), 2.09-1.91(m, 1H), 1.49 (s, 9H), 1.17 (t, J = 7.2 Hz, 3H).  85(S)-5-(tert-butyl)-N-(2- ethyl-8-(2-((1-methyl- 1H-pyrazol-4-yl)amino)pyrimidin-4- yl)-2,3,4,5-tetrahydro- 1H-benzo[c]azepin- 5-yl)-1,3,4-oxadiazole-2- carboxamide

LCMS: Rt 3.9 min, m/z 516.10. ¹H NMR (400 MHz, METHANOL-d₄) δ: 8.39 (d,J = 5.3 Hz, 1H), 8.04-7.98 (m, 2H), 7.96 (s, 1H), 7.62 (s, 1H), 7.45 (d,J = 8.0 Hz, 1H), 7.20 (d, J = 5.3 Hz, 1H), 5.54 (d, J = 9.3 Hz, 1H),4.07 (s, 2H), 3.88 (s, 3H), 3.29- 3.20 (m, 1H), 3.10 (ddd, J = 13.2 Hz,10.5 Hz, 2.6 Hz, 1H), 2.66-2.50 (m, 2H), 2.25 (dtd, J = 14.0 Hz, 10.4Hz, 3.4 Hz, 1H), 2.01 (dt, J = 14.4 Hz, 2.3 Hz, 1H), 1.49 (s, 9 H), 1.18(t, J = 7.2 Hz, 3H).  86 5-(tert-butyl)-N-(2- ((S)-2-hydroxypropyl)-8-(2-((1-methyl-1H- pyrazol-4- yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro- 1H-benzo[c]azepin-5- yl)-1,3,4-oxadiazole-2-carboxamide

ESI-MS (M + H)⁺: 546.3. ¹H NMR (400 MHz, CD₃OD) δ: 8.33 (d, J = 5.2 Hz,1H), 7.94-7.90 (m, 3H), 7.61 (d, J = 2.0 Hz, 1H), 7.42 (d, J = 8.4 Hz,1H), 7.11 (dd, J = 5.2, 1.6 Hz, 1H), 5.55-5.52 (m, 1H), 4.12-3.93 (m,3H), 3.87 (s, 3H), 3.23-3.18 (m, 2H), 2.42-2.37 (m, 2H), 2.24-2.22 (m,1H), 1.93-1.91 (m, 1H), 1.48 (s, 9H), 1.13-1.09 (m, 3H).  875-(tert-butyl)-N-(2-((R)- 2-hydroxypropyl)-8-(2- ((1-methyl-1H-pyrazol-4- yl)amino)pyrimidin-4- yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin- 5-yl)- 1,3,4-oxadiazole-2- carboxamide

ESI-MS (M + H)⁺: 545.7. ¹H NMR (400 MHz, CD₃OD) δ: 8.30-8.28 (m, 1H),7.91-7.69 (m, 3H), 7.52 (s, 1H), 7.36 (d, J = 8.4 Hz, 1H), 7.11 (s, 1H),5.46 (d, J = 10.0 Hz, 1H), 4.11- 3.85 (m, 3H), 3.79 (s, 3H), 3.10-3.06(m, 2H), 2.33-2.14 (m, 3H), 1.86- 1.83 (m, 1H), 1.39 (s, 9H), 1.05-1.00(m, 3H).  88 5-(tert-butyl)-N-(2-(2- hydroxy-2- methylpropyl)-8- (2-((1-methyl-1H-pyrazol-4- yl)amino)pyrimidin-4- yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin- 5-yl)- 1,3,4-oxadiazole-2- carboxamide

ESI-MS (M + H)⁺: 559.7. ¹H NMR (400 MHz, CD₃OD) δ: 8.27-8.25 (m, 1H),7.84-7.81 (m, 3H), 7.52 (s, 1H), 7.34-7.33 (m, 1H), 7.07-7.05 (m, 1H),5.46 (d, J = 10.0 Hz, 1H), 4.11- 3.97 (m, 2H), 3.77 (s, 3H), 3.21-3.17(m, 2H), 2.37-2.27 (m, 2H), 2.13- 2.12 (m, 1H), 1.84-1.80 (m, 1H), 1.38(s, 9H), 1.09 (s, 6H).  89a 5-tert-butyl-1,3,4- oxadiazole-2-carboxylicacid {(R)-2-(2-hydroxy- 2-methyl-propyl)- 8-[2-(1- methyl-1H-pyrazol-4-ylamino)-pyrimidin-4- yl]-2,3,4,5-tetrahydro- 1H-2-benzazepin-5-yl}-amide

LCMS: Rt 0.87 min, m/z 560.3. ¹H NMR (400 MHz, METHANOL-d4) δ: 8.42 (br.s., 1H), 7.90-8.13 (m, 3H), 7.64 (s, 1H), 7.47 (d, J = 8.03 Hz, 1H),7.22 (br. s., 1H), 5.58 (d, J = 9.79 Hz, 1H), 4.07-4.34 (m, 2H), 3.90(s, 3H), 2.45 (q, J = 14.31 Hz, 2H), 2.18-2.32 (m, 3H), 1.95 (d, J =13.80 Hz, 1H), 1.50 (s, 9H), 1.22 (br. s., 6H).  89b(S)-5-(tert-butyl)-N-(2- (2-hydroxy-2- methylpropyl)- 8-(2-((1-methyl-1H-pyrazol-4- yl)amino)pyrimidin-4- yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin- 5-yl)- 1,3,4-oxadiazole-2- carboxamide

LCMS: Rt 0.87 min, m/z 560.3. 1H NMR (400 MHz, METHANOL-d4) δ: 8.43 (br.s., 1H), 8.02 (s, 3H), 7.64 (s, 1H), 7.47 (d, J = 8.03 Hz, 1H), 7.23(br. s., 1H), 5.58 (d, J = 9.54 Hz, 1H), 4.05-4.38 (m, 2H), 3.90 (s,3H), 2.45 (q, J = 14.06 Hz, 2H), 2.27 (d, J = 2.51 Hz, 1H), 1.95 (d, J =13.80 Hz, 1H), 1.50 (s, 9H), 1.21 (s, 6H).  90 5-(tert-butyl)-N-(2-(3-hydroxypropyl)- 8-(2-((1- methyl-1H-pyrazol-4- yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro- 1H-benzo[c]azepin- 5-yl)- 1,3,4-oxadiazole-2-carboxamide

ESI-MS (M + H)⁺: 545.7. ¹H NMR (400 MHz, CD₃OD) δ: 8.29 (d, J = 5.2 Hz,1H), 7.91-7.88 (m, 2H), 7.85 (s, 1H), 7.53 (s, 1H), 7.35 (d, J = 8.0 Hz,1H), 7.10 (d, J = 5.2 Hz, 1H), 5.46-5.42 (m, 1H), 4.02-3.93 (m, 2H),3.78 (s, 3H), 3.51 (t, J = 6.0 Hz, 2H), 3.20-3.15 (m, 1H), 3.04-3.00 (m,1H), 2.53-2.47 (m, 2H), 2.19- 2.11 (m, 1H), 1.90-1.87 (m, 1H), 1.74-1.68(m, 2H), 1.38 (s, 9H).  91 5-(tert-butyl)-N- (8-(2-((1-methyl-1H-pyrazol-4- yl)amino)pyrimidin-4- yl)-2-(2,2,2-trifluoroethyl)-2,3,4,5- tetrahydro-1H- benzo[c]azepin-5-yl)-1,3,4-oxadiazole-2- carboxamide

ESI-MS (M + H)⁺: 570.2. ¹H NMR (400 MHz, CDCl₃) δ: 8.37 (d, J = 5.2 Hz,1H), 7.83-7.76 (m, 4H), 7.46 (s, 1H), 7.42 (d, J = 8.0 Hz, 1H), 6.99 (d,J = 5.2 Hz, 1H), 6.85 (s, 1H), 5.56-5.52 (m, 1H), 4.23-4.19 (m, 1H),4.08-4.04 (m, 1H), 3.85 (s, 3H), 3.28-3.04 (m, 4H), 2.23-2.18 (m, 1H),2.02-1.95 (m, 1H), 1.40 (s, 9H).  92 N-(8-(2-((1H-pyrazol-4-yl)amino)pyrimidin-4- yl)-2-(oxetan-3-yl)- 2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-5- (tert-butyl)-1,3,4- oxadiazole-2- carboxamide

ESI-MS (M + H)⁺: 530.3. ¹H NMR (400 MHz, DMSO-d₆) δ: 9.83 (d, J = 8.4Hz, 1H), 9.47 (s, 1H), 8.47 (d, J = 8.8 Hz, 1H), 7.99 (d, J = 8.8 Hz,1H), 7.96 (s, 1H), 7.91 (s, 1H), 7.65 (s, 1H), 7.39 (d, J = 8.0 Hz, 1H),7.27 (d, J = 5.2 Hz, 2H), 5.40 (t, J = 9.6 Hz, 1H), 4.58 (t, J = 6.4 Hz,1H), 4.52-4.45 (m, 3H), 3.90-3.62 (m, 3H), 2.95-2.92 (m, 1H), 2.83-2.77(m, 1H), 2.13-2.05 (m, 1H), 1.88- 1.85 (m, 1H), 1.42 (s, 9H).  93(R)-5-(tert-butyl)-N-(8- (2-((5,6-dihydro-4H- pyrrolo[1,2-b]pyrazol-3-yl)amino)pyrimidin-4- yl)-2-(2-hydroxyethyl)- 2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)- 1,3,4-oxadiazole-2- carboxamide

ESI-MS (M + H)⁺: 557.7. ¹H NMR (400 MHz, CD₃OD) δ: 8.36 (d, J = 5.2 Hz,1H), 8.04-8.02 (m, 2H), 7.69 (s, 1H), 7.48 (d, J = 8.0 Hz, 1H), 7.22 (d,J = 5.2 Hz, 1H), 5.60-5.57 (m, 1H), 4.29-4.13 (m, 4H), 3.77 (t, J = 6.0Hz, 2H), 3.35-3.33 (m, 2H), 2.95 (t, J = 7.2 Hz, 2H), 2.78-2.76 (m, 2H),2.66-2.62 (m, 2H), 2.34- 2.28 (m, 1H), 2.08-2.01 (m, 1H), 1.50 (s, 9H). 94 (R)-1-(tert-butyl)- N-(8- (2-((5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol- 3-yl)amino)pyrimidin- 4-yl)-2-(2-hydroxyethyl)-2,3,4,5- tetrahydro-1H- benzo[c]azepin-5-yl)-1H-1,2,3-triazole-4- carboxamide

ESI-MS (M + H)⁺: 556.7. ¹H NMR (400 MHz, CD₃OD) δ: 8.45 (s, 1H), 8.27(d, J = 5.2 Hz, 1H), 7.91-7.87 (m, 2H), 7.59 (s, 1H), 7.37 (d, J = 8.0Hz, 1H), 7.14 (d, J = 5.6 Hz, 1H), 5.49 (d, J = 9.6 Hz, 1H), 4.13- 3.99(m, 4H), 3.65 (t, J = 6.0 Hz, 2H), 3.20-3.05 (m, 2H), 2.86 (t, J = 7.2Hz, 2H), 2.62-2.52 (m, 4H), 2.21-2.17 (m, 1H), 1.93-1.89 (m, 1H), 1.65(s, 9H).  95 N-(2-methyl-8-(2-((1- methyl-1H-pyrazol-4-yl)amino)pyrimidin-4- yl)-2,3,4,5-tetrahydro- 1H-benzo[c]azepin-5-yl)-5-(1-methylcyclopropyl)- 1,3,4-oxadiazole-2- carboxamide

ESI-MS (M + H)⁺: 530.2. ¹H NMR (400 MHz, CD₃OD) δ: 8.39 (d, J = 5.2 Hz,1H), 8.00-7.97 (m, 3H), 7.63 (s, 1H), 7.44 (d, J = 8.0 Hz, 1H), 7.19 (d,J = 5.6 Hz, 1H), 5.53 (d, J = 10.0 Hz, 1H), 4.18-4.06 (m, 2H), 3.90 (s,3H), 3.73 (t, J = 6.0 Hz, 2H), 3.28-3.19 (m, 2H), 2.67-2.62 (m, 2H),2.28-2.24 (m, 1H), 1.98-1.95 (m, 1H), 1.61 (s, 3H), 1.45-1.42 (m, 2H),1.13-1.10 (m, 2H).  96 5-(tert-butyl)-N-(8- (2-((1- ethyl-1H-pyrazol-4-yl)amino)pyrimidin-4- yl)-2-(tetrahydrofuran- 3-yl)- 2,3,4,5-tetrahydro-1H-benzo[c]azepin- 5-yl)- 1,3,4-oxadiazole-2- carboxamide

ESI-MS (M + H)⁺: 572.3. ¹H NMR (400 MHz, CD₃OD) δ: 8.42 (d, J = 5.2 Hz,1H), 8.05-8.03 (m, 3H), 7.65 (s, 1H), 7.48 (d, J = 7.6 Hz, 1H), 7.24 (d,J = 5.2 Hz, 1H), 5.60-5.57 (m, 1H), 4.21-3.97 (m, 6H), 3.78- 3.70 (m,2H), 3.32-3.14 (m, 3H), 2.33-1.96 (m, 4H), 1.51-1.47 (m, 12H).  975-(tert-butyl)-N-((R)-8- (2-((1-ethyl-1H-pyrazol-4-yl)amino)pyrimidin-4- yl)-2-((R*)- tetrahydrofuran-3-yl)-2,3,4,5-tetrahydro-1H- benzo[c]azepin-5-yl)- 1,3,4-oxadiazole-2-carboxamide

LCMS: Rt 0.90 min, m/z 572.10. ¹H NMR (300 MHz, METHANOL-d₄) δ: 8.41 (d,J = 5.3 Hz, 1H), 8.07-7.98 (m, 3H), 7.65 (s, 1H), 7.48 (d, J = 7.6 Hz,1H), 7.22 (d, J = 5.3 Hz, 1H), 5.56 (br d, J = 9.1 Hz, 1H), 4.58 (s,1H), 4.23-4.07 (m, 4H), 4.13-3.90 (m, 2H), 3.82-3.63 (m, 2H), 3.27- 3.05(m, 2H), 2.42-2.11 (m, 2H), 2.11-1.90 (m, 2H), 1.51-1.43 (m, 12H).  985-(tert-butyl)-N-(8- (2-((1- ethyl-1H-pyrazol-4- yl)amino)pyrimidin-4-yl)-2-(2-hydroxyethyl)- 2,3,4,5-tetrahydro-1H- benzo[c]azepin-5-yl)-1,3,4-oxadiazole-2- carboxamide

ESI-MS (M + H)⁺: 545.7. ¹H NMR (400 MHz, CD₃OD) δ: 8.42 (d, J = 5.2 Hz,1H), 8.04-8.02 (m, 3H), 7.66 (s, 1H), 7.47 (d, J = 8.0 Hz, 1H), 7.23 (d,J = 5.2 Hz, 1H), 5.58-5.56 (m, 1H), 4.23-4.10 (m, 4H), 3.74 (t, J = 6.0Hz, 1H), 3.25-3.22 (m, 2H), 2.71-2.63 (m, 2H), 2.32-2.27 (m, 1H),2.02-1.98 (m, 1H), 1.40-1.47 (m, 12H).  99 5-(tert-butyl)-N-(2-methyl-8-(2-((1-methyl- 1H-pyrazol-4- yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro- 1H-benzo[c]azepin- 5-yl)- 1,3,4-oxadiazole-2-carboxamide

ESI-MS (M + H)⁺: 502.2. ¹H NMR (400 MHz, CD₃OD) δ: 8.43 (d, J = 5.2 Hz,1H), 8.07-8.05 (m, 2H), 7.99 (s, 1H), 7.65 (s, 1H), 7.49 (d, J = 8.4 Hz,1H), 7.25 (d, J = 5.6 Hz, 1H), 5.56 (d, J = 9.6 Hz, 1H), 4.13-4.09 (m,1H), 3.97-3.93 (m, 1H), 3.90 (s, 3H), 3.21-3.18 (m, 1H), 3.10-3.05 (m,1H), 2.42 (s, 3H), 2.30-2.26 (m, 1H), 2.05-2.01 (m, 1H), 1.52 (s, 9H).100 (R)-5-(tert-butyl)-N-(8- (2-((1,5-dimethyl-1H- pyrazol-4-yl)amino)pyrimidin-4- yl)-2-(2-hydroxyethyl)- 2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)- 1,3,4-oxadiazole-2- carboxamide

ESI-MS (M + H)⁺: 545.7. ¹H NMR (400 MHz, CD₃OD) δ: 8.32 (d, J = 5.2 Hz,1H), 8.01-7.99 (m, 2H), 7.60 (s, 1H), 7.44 (d, J = 8.0 Hz, 1H), 7.23 (d,J = 5.6 Hz, 1H), 5.57-5.54 (m, 1H), 4.21-4.07 (m, 2H), 3.82 (s, 3H),3.73 (t, J = 6.0 Hz, 2H), 3.30- 3.21 (m, 2H), 2.68-2.63 (m, 2H),2.30-2.27 (m, 1H), 2.24 (s, 3H), 2.01-1.96 (m, 1H), 1.51 (s, 9H). 101(R)-1-(tert-butyl)- N-(8- (2-((1,5-dimethyl-1H- pyrazol-4-yl)amino)pyrimidin-4- yl)-2-(2-hydroxyethyl)- 2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)- 1H-1,2,3-triazole-4- carboxamide

ESI-MS (M + H)⁺: 544.7. ¹H NMR (400 MHz, CDCl₃) δ: 8.47 (br, 1H), 8.36(d, J = 5.2 Hz, 1H), 8.16 (s, 1H), 7.80-7.78 (m, 2H), 7.67 (s, 1H), 7.45(d, J = 7.6 Hz, 1H), 7.02 (d, J = 5.2 Hz, 1H), 6.45 (s, 1H), 5.59 (t, J= 8.8 Hz, 1H), 4.12-4.02 (m, 2H), 3.81 (s, 3H), 3.77-3.68 (m, 2H),3.28-3.24 (m, 1H), 2.99-2.96 (m, 1H), 2.79- 2.76 (m, 2H), 2.33-2.26 (m,1H), 2.22 (s, 3H), 2.08-2.01 (m, 1H), 1.70 (s, 9H). 102(R)-5-(tert-butyl)-N-(8- (2-((1,3-dimethyl-1H- pyrazol-4-yl)amino)pyrimidin-4- yl)-2-(oxetan-3-yl)- 2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)- 1,2,4-oxadiazole-3- carboxamide

ESI-MS (M + H)⁺: 558.3. ¹H NMR (400 MHz, CD₃OD) δ: 8.38 (d, J = 5.6 Hz,1H), 8.02 (d, J = 8.0 Hz, 1H), 7.95 (s, 1H), 7.84 (s, 1H), 7.46 (d, J =8.0 Hz, 1H), 7.24 (d, J = 5.2 Hz, 1H), 5.61 (d, J = 9.2 Hz, 1H), 4.76(t, J = 6.4 Hz, 1H), 4.70-4.66 (m, 3H), 3.96-3.81 (m, 3H), 3.84 (s, 3H),3.08-3.02 (m, 1H), 2.87-2.81 (m, 1H), 2.27-2.24 (m, 1H), 2.22 (s, 3H),207-203 (m, 1H), 1.15 (s, 9H). 103 (R)-1-(tert-butyl)-N-(8-(2-((1,3-dimethyl-1H- pyrazol-4- yl)amino)pyrimidin-4-yl)-2-(oxetan-3-yl)- 2,3,4,5-tetrahydro-1H- benzo[c]azepin- 5-yl)-1H-1,2,3-triazole-4- carboxamide

ESI-MS (M + H)⁺: 557.3. ¹H NMR (400 MHz, CD₃OD) δ: 8.53 (s, 1H), 8.37(d, J = 5.2 Hz, 1H), 8.00 (d, J = 7.6 Hz, 1H), 7.95 (s, 1H), 7.84 (s,1H), 7.47 (d, J = 8.0 Hz, 1H), 7.24 (d, J = 5.6 Hz, 1H), 5.59 (d, J =9.6 Hz, 1H), 4.76 (t, J = 6.4 Hz, 1H), 4.70-4.67 (m, 3H), 3.98-3.81 (m,3H), 3.84 (s, 3H), 3.08-3.05 (m, 1H), 2.92-2.87 (m, 1H), 2.27-2.21 (m,1H), 2.19 (s, 3H), 2.06-2.03 (m, 1H), 1.74 (s, 9H). 104(R)-5-(tert-butyl)-N-(8- (2-((1,3-dimethyl-1H- pyrazol-4-yl)amino)pyrimidin-4- yl)-2-(2-hydroxyethyl)- 2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)- 1,2,4-oxadiazole-3- carboxamide

ESI-MS (M + H)⁺: 546.3. ¹H NMR (400 MHz, CD₃OD) δ: 8.37 (d, J = 4.8 Hz,1H), 8.01 (s, 1H), 8.00 (d, J = 8.4 Hz, 1H), 7.85 (s, 1H), 7.44 (d, J =8.0 Hz, 1H), 7.25 (d, J = 5.6 Hz, 1H), 5.59 (d, J = 9.6 Hz, 1H), 4.21-4.08 (m, 2H), 3.85 (s, 3H), 3.74 (t, J = 6.0 Hz, 2H), 3.27-3.17 (m, 2H),2.71-2.63 (m, 2H), 2.30-2.25 (m, 1H), 2.22 (s, 3H), 1.99-1.96 (m, 1H),1.52 (s, 9H). 105 (R)-1-(tert-butyl)-N-(2- (2-hydroxyethyl)-8-(2-((1-isopropyl-1H- pyrazol-4- yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro- 1H-benzo[c]azepin- 5-yl)- 1H-1,2,3-triazole-4-carboxamide

ESI-MS (M + H)⁺: 559.3. ¹H NMR (400 MHz, CDCl₃) δ: 8.51 (br, 1H), 8.41(d, J = 4.8 Hz, 1H), 8.17 (s, 1H), 7.95 (s, 1H), 7.83-7.82 (m, 2H), 7.56(s, 1H), 7.48 (d, J = 8.4 Hz, 1H), 7.15 (s, 1H), 7.02 (d, J = 5.2 Hz,1H), 5.61 (t, J = 8.0 Hz, 1H), 4.53-4.46 (m, 1H), 4.14-4.02 (m, 2H),3.79-3.70 (m, 2H), 3.29-3.24 (m, 1H), 2.98-2.95 (m, 1H), 2.79- 2.77 (m,2H), 2.32-2.27 (m, 1H), 2.06-2.03 (m, 1H), 1.68 (s, 9H), 1.55 (d, J =6.4 Hz, 6H). 106 5-(tert-butyl)-N-((R)-2- ((R)-2-hydroxy- propyl)-8-(2-((1-methyl-1H- pyrazol-4- yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro- 1H-benzo[c]azepin- 5-yl)- 1,3,4-oxadiazole-2-carboxamide

ESI-MS (M + H)⁺: 546.3. ¹H NMR (400 MHz, CD₃OD) δ: 8.39 (d, J = 5.2 Hz,1H), 8.00-7.97 (m, 3H), 7.64 (s, 1H), 7.45 (d, J = 8.0 Hz, 1H), 7.19 (d,J = 5.2 Hz, 1H), 5.57-5.55 (m, 1H), 4.21-4.09 (m, 2H), 3.99- 3.97 (m,1H), 3.90 (s, 3H), 3.28-3.23 (m, 2H), 2.40-2.37 (m, 2H), 2.28- 2.25 (m,1H), 1.97-1.94 (m, 1H), 1.48 (s, 9H), 1.13-1.12 (m, 3H). 107(R)-5-(tert-butyl)-N-(2- (cyclopropylmethyl)-8- (2-((1-methyl-1H-pyrazol-4- yl)amino)pyrimidin-4- yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5- yl)-1,3,4-oxadiazole-2- carboxamide

ESI-MS (M + H)⁺: 542.1. ¹H NMR (300 MHz, METHANOL-d₄) δ: 8.45 (d, J =5.3 Hz, 1H), 8.28-8.23 (m, 2H), 7.92 (s, 1H), 7.70-7.61 (m, 2H), 7.28(d, J = 5.7 Hz, 1H), 5.72 (br s, 1H), 4.83-4.72 (m, 2H), 3.89 (s, 3H),3.87-3.67 (m, 2H), 3.25-3.14 (m, 1H), 2.46 (br s, 2H), 1.50 (s, 10H),1.32-1.17 (m, 1H), 0.85 (br s, 2H), 0.52 (br s, 2H). 1081-(tert-butyl)-N-((S)-8- (2-((1-methyl-1H- pyrazol-4-yl)amino)pyrimidin-4- yl)-2-((S*)- tetrahydrofuran-3-yl)-2,3,4,5-tetrahydro-1H- benzo[c]azepin- 5-yl)-1H- 1,2,3-triazole-4-carboxamide

LCMS: Rt 0.82 min, m/z 557.00. ¹H NMR (400 MHz, METHANOL-d₄) δ: 8.51 (s,1H), 8.41 (d, J = 5.4 Hz, 1H), 8.11-8.00 (m, 2H), 7.97 (s, 1H),7.67-7.58 (m, 1H), 7.49 (d, J = 8.0 Hz, 1H), 7.23 (d, J = 5.3 Hz, 1H),5.66-5.54 (m, 1H), 4.58 (br s, 1H), 4.28-4.108 (m, 2H), 4.03 (td, J =8.7 Hz, 3.8 Hz, 1H), 3.99-3.93 (m, 1H), 3.89 (s, 3H), 3.86-3.70 (m, 2H),3.47-3.38 (m, 1H), 3.27-3.17 (m, 1H), 2.37-2.17 (m, 2H), 2.16-1.96 (m,2H), 1.73 (m, 9H). 109 1-(tert-butyl)-N-((S)-8- (2-((1-methyl-1H-pyrazol-4- yl)amino)pyrimidin-4- yl)-2-((R*)- tetrahydrofuran-3-yl)-2,3,4,5-tetrahydro-1H- benzo[c]azepin-5-yl )- 1H-1,2,3-triazole-4-carboxamide

LCMS: Rt 0.82 min, m/z 557.10. ¹H NMR (400 MHz, METHANOL-d₄) δ: 8.51 (s,1H), 8.46-8.37 (m, 1H), 8.09-8.00 (m, 2H), 7.99 (s, 1H), 7.65-7.58 (m,1H), 7.49 (d, J = 8.0 Hz, 1H), 7.22 (d, J = 5.3 Hz, 1H), 5.59 (br d, J =9.5 Hz, 1H), 4.58 (s, 1H), 4.26-4.12 (m, 2H), 4.07-3.94 (m, 2H), 3.89(s, 3H), 3.86-3.71 (m, 2H), 3.46-3.37 (m, 1H), 3.26-3.19 (m, 1H),2.36-2.16 (m, 2H), 2.14- 1.95 (m, 2H), 1.73 (s, 9H). 110(R)-5-(tert-butyl)-N-(8- (2-((1,3-dimethyl-1H- pyrazol-4-yl)amino)pyrimidin-4- yl)-2-(2,2,2- trifluoroethyl)-2,3,4,5-tetrahydro-1H- benzo[c]azepin-5-yl)- 1,3,4-oxadiazole-2- carboxamide

ESI-MS (M + H)⁺: 584.3. ¹H NMR (400 MHz, CD₃OD) δ: 8.38 (d, J = 5.2 Hz,1H), 8.03 (d, J = 8.4 Hz, 1H), 7.98 (s, 1H), 7.84 (s, 1H), 7.49 (d, J =8.0 Hz, 1H), 7.25 (d, J = 5.6 Hz, 1H), 5.59 (d, J = 9.6 Hz, 1H),4.37-4.34 (m, 1H), 4.13-4.10 (m, 1H), 3.84 (s, 3H), 3.46-3.41 (m, 2H),3.15-3.08 (m, 2H), 2.25-2.17 (m, 1H), 2.22 (s, 3H), 1.97-1.93 (m, 1H),1.51 (s, 9H). 111 5-(tert-butyl)-N-(2- (2-((1- methyl-1H-pyrazol-4-yl)amino)pyrimidin-4- yl)-6,7,8,9-tetrahydro- 5H-benzo[7]annulen-5-yl)-1,3,4-oxadiazole-2- carboxamide

LCMS: Rt 1.23 min.; (M + H)⁺ 487.0; ¹H NMR (400 MHz, METHANOL- d4) δ:9.70 (br. s., 1H), 8.34 (d, J = 5.77 Hz, 1H), 8.02 (s, 2H), 7.97 (s,1H), 7.69 (s, 1H), 7.47 (d, J = 8.53 Hz, 1H), 7.41 (s, 1H), 5.44 (t, J =8.28 Hz, 1H), 3.93 (s, 3H), 2.87- 3.22 (m, 2H), 1.77-2.28 (m, 4H), 1.51(s, 11H). 112 N-(2-(2-((1H-pyrazol-4- yl)amino)pyrimidin-4-yl)-6,7,8,9-tetrahydro- 5H-benzo[7]annulen-5- yl)-5-(tert-butyl)-1,2,4-oxadiazole-3- carboxamide

ESI-MS (M + H)⁺: 473.1. ¹H NMR (400 MHz, CD₃OD) δ: 8.41 (d, J = 5.2 Hz,1H), 8.07 (br, 1H), 7.96-7.95 (m, 2H), 7.76 (br, 1H), 7.40 (d, J = 8.4Hz, 1H), 7.22 (d, J = 5.6 Hz, 1H), 5.44 (d, J = 9.6 Hz, 1H), 3.06- 3.03(m, 2H), 2.10-1.91 (m, 5H), 1.53 (s, 9H), 1.49-1.46 (m, 1H). 1135-(tert-butyl)-N-(2- (2-((5- methyl-4,5,6,7- tetrahydropyrazolo[1,5-a]pyrazin-3- yl)amino)pyrimidin-4- yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5- yl)-1,2,4-oxadiazole-3- carboxamide

ESI-MS (M + H)⁺: 542.2. ¹H NMR (400 MHz, CD₃OD) δ: 8.34 (d, J = 5.2 Hz,1H), 7.94-7.91 (m, 2H), 7.70 (s, 1H), 7.38 (d, J = 8.0 Hz, 1H), 7.25 (d,J = 5.6 Hz, 1H), 5.45-5.42 (m, 1H), 4.23-4.21 (m, 2H), 3.67 (s, 2H),3.02-2.99 (m, 4H), 2.49 (s, 3H), 2.06-1.92 (m, 5H), 1.54 (s, 9H),1.51-1.42 (m, 1H). 114 N-(2-(2-((1H-pyrazol-4- yl)amino)pyrimidin-4-yl)-6,7,8,9-tetrahydro- 5H-benzo[7]annulen-5- yl)-5-(tert-butyl)-1,3,4-oxadiazole-2- carboxamide

ESI-MS (M + H)⁺: 472.7. ¹H NMR (400 MHz, DMSO-d₆) δ: 12.46 (s, 1H), 9.89(d, J = 8.0 Hz, 1H), 9.45 (s, 1H), 8.45 (d, J = 5.2 Hz, 1H), 7.96-7.91(m, 3H), 7.63-7.62 (m, 1H), 7.37 (d, J = 8.0 Hz, 1H), 7.24 (d, J = 5.2Hz, 1H), 5.28-5.24 (m, 1H), 2.97-2.96 (m, 5H), 2.00-1.77 (m, 5H), 1.42(s, 9H), 1.33-1.30 (m, 1H). 115 1-(tert-butyl)-N- (2-(2-((1-methyl-1H-pyrazol-4- yl)amino)pyrimidin-4- yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5- yl)-1H-1,2,3-triazole-4- carboxamide

ESI-MS (M + H)⁺: 486.2. ¹H NMR (400 MHz, CDCl₃) δ: 8.39 (d, J = 5.2 Hz,1H), 8.16 (s, 1H), 7.90 (s, 1H), 7.81 (s, 1H), 7.79 (s, 1H), 7.68 (d, J= 8.4 Hz, 1H), 7.54 (s, 1H), 7.42 (d, J = 8.0 Hz, 1H), 7.05 (d, J = 5.2Hz, 1H), 6.91 (s, 1H), 5.46-5.42 (m, 1H), 3.91 (s, 3H), 3.04-3.01 (m,2H), 2.05-1.88 (m, 6H), 1.72 (s, 9H). 116 5-(tert-butyl)-4-methyl-N-(2-(2-((1-methyl-1H- pyrazol-4- yl)amino)pyrimidin-4-yl)-6,7,8,9-tetrahydro- 5H-benzo[7]annulen-5- yl)-4H-1,2,4-triazole-3-carboxamide

ESI-MS (M + H)⁺: 500.3. ¹H NMR (400 MHz, CD₃OD) δ: 8.27 (d, J = 5.2 Hz,1H), 7.85-7.81 (m, 3H), 7.53 (s, 1H), 7.30 (d, J = 8.8 Hz, 1H), 7.08 (d,J = 5.2 Hz, 1H), 5.26-5.24 (m, 1H), 4.04 (s, 3H), 3.77 (s, 3H),2.95-2.93 (m, 2H), 1.97-1.79 (m, 5H), 1.36-1.33 (m, 1H), 1.30 (s, 9H).117 2-isopropyl-N-(2-(2- ((1-methyl-1H-pyrazol-4- yl)amino)pyrimidin-4-yl)-6,7,8,9-tetrahydro- 5H-benzo[7]annulen-5- yl)-2H-1,2,3-triazole-4-carboxamide

ESI-MS (M + H)⁺: 472.2. ¹H NMR (400 MHz, CDCl₃) δ: 8.41 (d, J = 5.2 Hz,1H), 8.06 (s, 1H), 7.87-7.81 (m, 3H), 7.55 (s, 1H), 7.40 (d, J = 7.6 Hz,1H), 7.20-7.18 (m, 1H), 7.06 (d, J = 5.2 Hz, 1H), 6.99 (s, 1H), 5.45-5.41 (m, 1H), 4.91-4.85 (m, 1H), 3.91 (s, 3H), 3.08-2.96 (m, 2H),2.03-1.86 (m, 5H), 1.67-1.66 (m, 1H), 1.63 (d, J = 6.8 Hz, 6H). 118a**Racemic mixture of 5- (tert-butyl)-N- ((5R,8S)-8-fluoro-2-(2-((1-methyl- 1H-pyrazol-4- yl)amino)pyrimidin-4-yl)-6,7,8,9-tetrahydro- 5H-benzo[7]annulen-5- yl)-1,3,4-oxadiazole-2-carboxamide and 5-(tert- butyl)-N-((5S,8R)-8- fluoro-2-(2-((1-methyl-1H-pyrazol-4- yl)amino)pyrimidin-4- yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5- yl)-1,3,4-oxadiazole-2- carboxamide

ESI-MS (M + H)⁺: 505.2. ¹H NMR (400 MHz, CDCl₃) δ: 8.44 (d, J = 5.2 Hz,1H), 7.90-7.88 (m, 3H), 7.60 (d, J = 7.6 Hz, 1H), 7.55 (s, 1H), 7.42 (d,J = 8.0 Hz, 1H), 7.08 (d, J = 5.2 Hz, 1H), 6.91 (s, 1H), 5.38 (d, J =8.0 Hz, 1H), 4.91 (d, J = 47.2 Hz, 1H), 3.92 (s, 3H), 3.45-3.29 (m, 2H),2.32-2.20 (m, 3H), 2.00-1.93 (m, 1H), 1.48 (s, 9H). 118b** Racemicmixture of 5- (tert-butyl)-N-((5R,8R)- 8-fluoro-2-(2- ((1-methyl-1H-pyrazol-4- yl)amino)pyrimidin-4- yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5- yl)-1,3,4-oxadiazole-2- carboxamide and 5-(tert-butyl)-N-((5S,8S)-8- fluoro-2-(2-((1- methyl-1H-pyrazol-4-yl)amino)pyrimidin-4- yl)-6,7,8,9-tetrahydro- 5H-benzo[7]annulen-5-yl)-1,3,4-oxadiazole-2- carboxamide

¹H NMR (400 MHz, CDCl₃) δ: 8.44 (d, J = 5.2 Hz, 1H), 7.92-7.88 (m, 3H),7.56-7.54 (m, 2H), 7.40 (d, J = 8.0 Hz, 1H), 7.07 (d, J = 5.2 Hz, 1H),6.89 (s, 1H), 5.40 (d, J = 9.6 Hz, 1H), 4.70 (d, J = 48.0 Hz, 1H), 3.92(s, 3H), 3.45-3.28 (m, 2H), 2.37-2.30 (m, 1H), 2.22-2.17 (m, 2H),1.95-1.92 (m, 1H), 1.49 (s, 9H). 119** Racemic mixture of N-((5R,8S)-8-fluoro-2-(2- ((1-methyl-1H-pyrazol-4- yl)amino)pyrimidin-4-yl)-6,7,8,9-tetrahydro- 5H-benzo[7]annulen-5- yl)-5-(1-methylcyclopropyl)- 1,2,4-oxadiazole-3- carboxamide and N-((5S,8R)-8-fluoro-2-(2- ((1-methyl-1H-pyrazol-4- yl)amino)pyrimidin-4-yl)-6,7,8,9-tetrahydro- 5H-benzo[7]annulen-5- yl)-5-(1-methylcyclopropyl)- 1,2,4-oxadiazole-3- carboxamide

ESI-MS (M + H)⁺: 503.2. ¹H NMR (400 MHz, CDCl₃) δ: 8.44 (d, J = 5.2 Hz,1H), 7.90-7.88 (m, 3H), 7.55 (s, 1H), 7.40-7.35 (m, 2H), 7.07 (d, J =5.2 Hz, 1H), 6.87 (s, 1H), 5.42 (d, J = 8.0 Hz, 1H), 4.90 (d, J = 48.8Hz, 1H), 3.92 (s, 3H), 3.39-3.33 (m, 2H), 2.33-2.17 (m, 3H), 1.95-1.92(m, 1H), 1.61 (s, 3H), 1.53-1.50 (m, 2H), 1.12-1.09 (m, 2H). 120**Racemic mixture of N- ((5S,8S)-8-fluoro-2-(2- ((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4- yl)-6,7,8,9-tetrahydro- 5H-benzo[7]annulen-5-yl)-5-(1- methylcyclopropyl)- 1,2,4-oxadiazole-3- carboxamide and N-((5R,8R)-8-fluoro-2-(2- ((1-methyl-1H-pyrazol-4- yl)amino)pyrimidin-4-yl)-6,7,8,9-tetrahydro- 5H-benzo[7]annulen-5- yl)-5-(1-methylcyclopropyl)- 1,2,4-oxadiazole-3- carboxamide

ESI-MS (M + H)⁺: 503.2. ¹H NMR (400 MHz, CDCl₃) δ: 8.44 (d, J = 5.6 Hz,1H), 7.91-7.87 (m, 3H), 7.55 (s, 1H), 7.36-7.30 (m, 2H), 7.07 (d, J =5.2 Hz, 1H), 6.87 (s, 1H), 5.43 (d, J = 8.4 Hz, 1H), 4.67 (d, J = 47.2Hz, 1H), 3.92 (s, 3H), 3.45-3.26 (m, 2H), 2.34-2.17 (m, 3H), 1.94-1.91(m, 1H), 1.63 (s, 3H), 1.55-1.53 (m, 2H), 1.13-1.12 (m, 2H). 1211-(tert-butyl)-N-((5R)-8- (2-((1-methyl-1H- pyrazol-4-yl)amino)pyrimidin-4- yl)-2-(tetrahydrofuran-3- yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)- 1H-1,2,3-triazole-4- carboxamide

ESI-MS (M + H)⁺: 557.3. ¹H NMR (400 MHz, CD₃OD) δ: 8.53 (s, 1H), 8.42(d, J = 5.2 Hz, 1H), 8.05-7.99 (m, 3H), 7.64 (s, 1H), 7.48 (d, J = 8.4Hz, 1H), 7.23 (d, J = 5.2 Hz, 1H), 5.58 (d, J = 10.4 Hz, 1H), 4.16- 4.09(m, 2H), 4.02-3.96 (m, 2H), 3.90 (s, 3H), 3.79-3.71 (m, 2H), 3.31-3.24(m, 2H), 3.15-3.10 (m, 1H), 2.31-2.17 (m, 2H), 2.07-1.97 (m, 2H), 1.74(s, 9H). 122 (R)-N-(2-(2-((1-methyl- 1H-pyrazol-4- yl)amino)pyrimidin-4-yl)-6,7,8,9-tetrahydro- 5H-benzo[7]annulen-5- yl)-5-(1-methylcyclopropyl)- 1,3,4-oxadiazole-2- carboxamide

ESI-MS (M + H)⁺: 485.2. ¹H NMR (400 MHz, CD₃OD) δ: 8.39 (d, J = 5.2 Hz,1H), 7.97-7.92 (m, 3H), 7.65 (s, 1H), 7.40 (d, J = 8.8 Hz, 1H), 7.20 (d,J = 5.2 Hz, 1H), 5.42-5.39 (m, 1H), 3.89 (s, 3H), 3.07-3.02 (m, 2H),2.10-1.86 (m, 5H), 1.62 (s, 3H), 1.47-1.43 (m, 3H), 1.13-1.10 (m, 2H).123 5-(tert-butyl)-N-(8- (2-((1- methyl-1H-pyrazol-4-yl)amino)pyrimidin-4- yl)-2,3,4,5-tetrahydro- 1H-benzo[c]azepin- 5-yl)-1,3,4-oxadiazole-2- carboxamide

ESI-MS (M + H)⁺: 488.3. ¹H NMR (400 MHz, CD₃OD) δ: 8.40 (d, J = 5.6 Hz,1H), 8.02-7.98 (m, 3H), 7.64 (s, 1H), 7.47 (d, J = 8.4 Hz, 1H), 7.21 (d,J = 5.2 Hz, 1H), 5.60-5.58 (m, 1H), 4.12 (s, 2H), 3.89 (s, 3H),3.39-3.37 (m, 1H), 3.28-3.21 (m, 2H), 2.15-2.09 (m, 2H), 1.51 (s, 9H).124* 5-(tert-butyl)-N-((R)-8- (2-((1-ethyl-1H-pyrazol-4-yl)amino)pyrimidin-4- yl)-2-((S*)- tetrahydrofuran-3-yl)-2,3,4,5-tetrahydro-1H- benzo[c]azepin-5-yl)- 1,3,4-oxadiazole-2-carboxamide

LCMS: Rt 0.90 min, m/z 572.10. ¹H NMR (300 MHz, METHANOL-d₄) δ: 8.41 (d,J = 5.3 Hz, 1H), 8.07-7.98 (m, 3H), 7.65 (s, 1H), 7.48 (d, J = 7.6 Hz,1H), 7.22 (d, J = 5.3 Hz, 1H), 5.56 (br d, J = 9.1 Hz, 1H), 4.58 (s,1H), 4.23-4.09 (m, 4H), 4.00-3.92 (m, 2H), 3.78-3.69 (m, 2H), 3.27- 3.05(m, 2H), 2.36-2.20 (m, 2H), 2.16-1.91 (m, 2H), 1.51-1.43 (m, 12H). 125N-(2-(2-hydroxyethyl)-8- (2-((1-methyl-1H- pyrazol-4-yl)amino)pyrimidin-4- yl)-2,3,4,5-tetrahydro- 1H-benzo[c]azepin-5-yl)-5- (1-methylcyclopropyl)- 1,3,4-oxadiazole-2- carboxamide

ESI-MS (M + H)⁺: 530.2. ¹H NMR (400 MHz, CD₃OD) δ: 8.39 (d, J = 5.2 Hz,1H), 8.00-7.97 (m, 3H), 7.63 (s, 1H), 7.44 (d, J = 8.0 Hz, 1H), 7.19 (d,J = 5.6 Hz, 1H), 5.53 (d, J = 10.0 Hz, 1H), 4.18-4.06 (m, 2H), 3.90 (s,3H), 3.73 (t, J = 6.0 Hz, 2H), 3.28-3.19 (m, 2H), 2.67-2.62 (m, 2H),2.28-2.24 (m, 1H), 1.98-1.95 (m, 1H), 1.61 (s, 3H), 1.45-1.42 (m, 2H),1.13-1.10 (m, 2H). 126 5-cyclobutyl-N-(2-(2- hydroxyethyl)-8-(2-((1-methyl-1H-pyrazol-4- yl)amino)pyrimidin-4- yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin- 5-yl)- 1,3,4-oxadiazole-2- carboxamide

ESI-MS (M + H)⁺: 529.7. ¹H NMR (400 MHz, CDCl₃) δ: 8.80 (br, 1H), 8.43(d, J = 5.2 Hz, 1H), 7.87 (s, 1H), 7.84-7.81 (m, 2H), 7.55 (s, 1H), 7.49(d, J = 8.0 Hz, 1H), 7.05 (d, J = 5.2 Hz, 1H), 6.90 (s, 1H), 5.59 (t, J= 8.0 Hz, 1H), 4.13-4.04 (m, 2H), 3.91 (s, 3H), 3.81-3.69 (m, 3H),3.27-3.20 (m, 1H), 2.96-2.91 (m, 1H), 2.81 (t, J = 4.8 Hz, 2H),2.52-2.32 (m, 5H), 2.17-2.02 (m, 3H), 1.60 (s, 9H). 127(R)-5-(tert-butyl)-N-(2- (2-ethoxyethyl)-8- (2-((1- methyl-1H-pyrazol-4-yl)amino)pyrimidin-4- yl)-2,3,4,5-tetrahydro- 1H-benzo[c]azepin-5-yl)-1,3,4-oxadiazole-2- carboxamide

ESI-MS (M + H)⁺: 560.1. ¹H NMR (300 MHz, METHANOL-d₄) δ: 8.39 (d, J =5.3 Hz, 1H), 8.02-7.95 (m, 3H), 7.62 (s, 1H), 7.45 (d, J = 7.9 Hz, 1H),7.19 (d, J = 5.3 Hz, 1H), 5.54 (br d, J = 9.1 Hz, 1H), 4.15 (d, J = 4.9Hz, 2H), 3.88 (s, 3H), 3.62 (t, J = 5.7 Hz, 2H), 3.50 (q, J = 6.8 Hz,2H), 3.26- 3.14 (m, 2H), 2.76-2.63 (m, 2H), 2.34-2.19 (m, 1H), 2.05-1.92(m, 1H), 1.50-1.47 (m, 9H), 1.16 (t, J = 7.0 Hz, 3H). 128(R)-5-(tert-butyl)-N-(7- (2-((1-methyl-1H- pyrazol-4-yl)amino)pyrimidin-4- yl)-3-(oxetan-3-yl)- 2,3,4,5-tetrahydro-1H-benzo[d]azepin-1-yl)- 1,3,4-oxadiazole-2- carboxamide

LCMS: Rt 0.87 min, m/z 544.2. ¹H NMR (400 MHz, METHANOL-d₄) δ: 8.39 (br.s., 1H), 7.81-8.04 (m, 3H), 7.64 (br. s., 1H), 7.50 (d, J = 8.03 Hz,1H), 7.17 (s, 1H), 5.25 (d, J = 6.53 Hz, 1H), 4.53-4.78 (m, 4H), 3.90(br. s., 3H), 3.67-3.83 (m, 1H), 2.20-3.28 (m, 6H), 1.37-1.66 (m, 9H).129 5-(tert-butyl)-N-(7-(2-((1- methyl-1H-pyrazol-4-yl)amino)pyrimidin-4- yl)-2,3,4,5-tetrahydro- 1H-benzo[d]azepin- 1-yl)-1,3,4-oxadiazole-2- carboxamide

ESI-MS (M + H)⁺: 488.00. ¹H NMR (400 MHz, DMSO-d₆) δ: 10.15 (d, J = 8.0Hz, 1H), 9.53 (s, 1H), 9.21 (br s, 2H), 8.49 (d, J = 5.3 Hz, 1H), 8.09-7.99 (m, 2H), 7.91 (s, 1H), 7.57 (br s, 1H), 7.48 (d, J = 8.3 Hz, 1H),7.27 (d, J = 5.3 Hz, 1H), 5.62 (br t, J = 8.4 Hz, 1H), 3.82 (s, 3H),3.61-3.47 (m, 2H), 3.44-3.21 (m, 3H), 3.13 (br d, J = 9.0 Hz, 1H), 1.43(s, 9H). 130 1-(tert-butyl)-N-(7- (2-((1- methyl-1H-pyrazol-4-yl)amino)pyrimidin-4- yl)-3-(oxetan-3-yl)- 2,3,4,5-tetrahydro-1H-benzo[d]azepin- 1-yl)-1H- 1,2,3-triazole-4- carboxamide

ESI-MS (M + H)⁺: 543.3. ¹H NMR (400 MHz, CD₃OD) δ: 8.44 (s, 1H), 8.41(d, J = 5.2 Hz, 1H), 7.98-7.92 (m, 3H), 7.65 (s, 1H), 7.56 (d, J = 8.0Hz, 1H), 7.21 (d, J = 5.2 Hz, 1H), 5.29-5.27 (m, 1H), 4.81-4.65 (m, 4H),3.90 (s, 3H), 3.86-3.79 (m, 1H), 3.10-2.87 (m, 4H), 2.57-2.37 (m, 2H),1.72 (s, 9H). 131 5-(tert-butyl)-N- (8-(2-((1- methyl-1H-pyrazol-4-yl)amino)pyrimidin-4- yl)-2-(tetrahydrofuran-3- yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin- 5-yl)- 1,3,4-thiadiazole-2- carboxamide

ESI-MS (M + H)⁺: 574.0. ¹H NMR (400 MHz, CDCl₃) δ: 8.42 (d, J = 5.2 Hz,1H), 8.38 (brs, 1H), 7.89-7.81 (m, 3H), 7.53 (s, 1H), 7.48 (d, J = 7.6Hz, 1H), 7.05 (d, J = 5.2 Hz, 1H), 6.96 (s, 1H), 5.62-5.56 (m, 1H),4.09-3.92 (m, 4H), 3.91 (s, 3H), 3.81-3.73 (m, 2H), 3.48-3.40 (m, 1H),3.23-3.08 (m, 1H), 2.99-2.95 (m, 1H), 2.35-2.28 (m, 1H), 2.19- 2.06 (m,2H), 2.00-1.95 (m, 1H), 1.51 (s, 9H). 132 5-(tert-butyl)-N-(3-methyl-7-(2-((1-methyl- 1H-pyrazol-4- yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro- 1H-benzo[d]azepin- 1-yl)- 1,3,4-oxadiazole-2-carboxamide

ESI-MS (M + H)⁺: 502.1. 133 (S)-5-(tert-butyl)-N-(8- (2-((1-methyl-1H-pyrazol-4- yl)amino)pyrimidin-4- yl)-2-(oxetan-3-yl)-2,3,4,5-tetrahydro-1H- benzo[c]azepin-5-yl)- 1,2,4-oxadiazole-3-carboxamide

ESI-MS (M + H)⁺: 544.0. ¹H NMR (400 MHz, METHANOL-d₄) δ: 8.40 (d, J =5.02 Hz, 1H), 7.87-8.09 (m, 3H), 7.63 (s, 1H), 7.45 (d, J = 8.28 Hz,1H), 7.20 (d, J = 5.27 Hz, 1H), 5.60 (s, 1H), 4.55-4.77 (m, 4H), 3.89(s, 3H), 3.75-3.85 (m, 3H), 2.75-3.10 (m, 2H), 1.89-2.42 (m, 2H), 1.51(s, 9H). 134 (S)-5-(tert-butyl)-N-(2- (3-hydroxy- cyclobutyl)-8-(2-((1-methyl-1H- pyrazol-4- yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro- 1H-benzo[c]azepin- 5-yl)- 1,3,4-oxadiazole-2-carboxamide

LCMS: Rt 4.5 min, m/z 558.00. ¹H NMR (400 MHz, METHANOL-d₄) δ: 8.41 (d,J = 5.3 Hz, 1H), 8.03-7.98 (m, 3H), 7.62 (s, 1H), 7.47-7.45 (m, 1H),7.22 (d, J = 5.3 Hz, 1H), 5.58- 5.48 (m, 1H), 4.58 (br s, 1H), 3.99 (brs, 1H), 3.89 (s, 3H), 3.25-3.21 (m, 1H), 2.97-2.91 (m, 1H), 2.63- 2.52(m, 2H), 2.25-2.15 (m, 2H), 2.05-1.98 (m, 1H), 1.87-1.79 (m, 2H), 1.49(s, 9H), 0.97-0.86 (m, 1H). 135 5-(tert-butyl)-N-(2- (2-((1-methyl-1H-pyrazol-4- yl)amino)pyrimidin-4- yl)-6,7,8,9-tetrahydro-1H-benzo[c]azepin- 5-yl)-1,3,4-thiadiazole- 2-carboxamide

ESI-MS (M + H)⁺: 503.2. ¹H NMR (400 MHz, CDCl₃) δ: 8.40 (d, J = 5.2 Hz,1H), 7.89-7.80 (m, 4H), 7.54 (s, 1H), 7.40 (d, J = 8.0 Hz, 1H), 7.06 (d,J = 5.2 Hz, 1H), 6.92 (s, 1H), 5.41-5.39 (m, 1H), 3.91 (s, 3H),3.03-3.00 (m, 2H), 2.00-1.84 (m, 6H), 1.53 (s, 9H). 1365-(tert-butyl)-N-((S)- 2-((S)-2-hydroxy- propyl)-8- (2-((1-methyl-1H-pyrazol-4- yl)amino)pyrimidin-4- yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin- 5-yl)- 1,3,4-oxadiazole-2- carboxamide

LCMS: Rt 0.85 min, m/z 546.3. ¹H NMR (400 MHz, METHANOL-d4) δ: 8.41 (br.s., 1H), 7.91-8.12 (m, 3H), 7.64 (br. s., 1H), 7.46 (d, J = 7.53 Hz,1H), 7.20 (br. s., 1H), 5.57 (d, J = 9.79 Hz, 1H), 4.08-4.36 (m, 2H),4.00 (br. s., 1H), 3.83-3.92 (m, 3H), 3.47-3.75 (m, 4H), 3.28 (br. s.,2H), 2.37-2.62 (m, 2H), 2.26 (br. s., 1H), 1.84-2.07 (m, 1H), 1.50 (s,9H), 0.95-1.24 (m, 4H). 137 (S)-5-(tert-butyl)-N-(8- (2-((1-methyl-1H-pyrazol-4- yl)amino)pyrimidin-4- yl)-2-(2,2,2- trifluoroethyl)-2,3,4,5-tetrahydro-1H- benzo[c]azepin-5-yl)- 1,2,4-oxadiazole-3- carboxamide

LCMS: Rt 1.36 min, m/z 570.3. ¹H NMR (400 MHz, METHANOL-d4) δ: 8.40 (br.s., 1H), 7.98 (d, J = 5.27 Hz, 3H), 7.62 (br. s., 1H), 7.46 (br. s.,1H), 7.18 (br. s., 1H), 5.60 (d, J = 8.78 Hz, 1H), 4.26-4.45 (m, 1H),4.02-4.20 (m, 1H), 3.89 (br. s., 3H), 3.39 (br. s., 1H), 3.11 (br. s.,2H), 2.24 (br. s., 1H), 1.97 (br. s., 1H), 1.52 (s, 9H). 138*5-(tert-butyl)-N-((S)-8- (2-((1-ethyl-1H-pyrazol-4-yl)amino)pyrimidin-4- yl)-2-((R*)- tetrahydrofuran-3-yl)-2,3,4,5-tetrahydro-1H- benzo[c]azepin-5-yl)- 1,3,4-oxadiazole-2-carboxamide

LCMS: Rt 0.90 min, m/z 572.0. ¹H NMR (300 MHz, METHANOL-d4) δ: 8.41 (d,J = 5.3 Hz, 1H), 8.07-7.97 (m, 3H), 7.65 (s, 1H), 7.48 (d, J = 7.6 Hz,1H), 7.22 (d, J = 5.3 Hz, 1H), 5.56 (br d, J = 8.7 Hz, 1H), 4.58 (s,1H), 4.22-4.08 (m, 4H), 4.03-3.92 (m, 2H), 3.78-3.69 (m, 2H), 3.27- 3.07(m, 2H), 2.36-2.14 (m, 2H), 2.06-1.91 (m, 2H), 1.53-1.43 (m, 12H). 139*5-(tert-butyl)-N-((S)-8- (2-((1-ethyl-1H-pyrazol-4-yl)amino)pyrimidin-4- yl)-2-((S*)- tetrahydrofuran-3-yl)-2,3,4,5-tetrahydro-1H- benzo[c]azepin-5-yl)- 1,3,4-oxadiazole-2-carboxamide

LCMS: Rt 0.90 min, m/z 572.0. ¹H NMR (300 MHz, METHANOL-d4) δ: 8.41 (d,J = 5.3 Hz, 1H), 8.04- 8.01 (m, 3H), 7.63 (s, 1H), 7.47 (d, J = 7.6 Hz,1H), 7.23 (d, J = 5.3 Hz, 1H), 5.57 (br d, J = 8.7 Hz, 1H), 4.58 (s,1H), 4.23-4.10 (m, 4H), 4.04- 3.93 (m, 2H), 3.78-3.70 (m, 2H), 3.25-3.07(m, 2H), 2.35-2.13 (m, 2H), 2.07-1.90 (m, 2H), 1.51-1.43 (m, 12H). 140tert-butyl 1-(5-(tert- butyl)-1,3,4-oxadiazole- 2-carboxamido)-7-(2-((1-methyl-1H-pyrazol-4- yl)amino)pyrimidin-4- yl)-1,2,4,5-tetrahydro-3H-benzo[d]azepine-3- carboxylate

ESI-MS (M + H)⁺: 588.10. ¹H NMR (400 MHz, CHLOROFORM-d) δ: 8.44 (d, J =5.3 Hz, 1H), 7.94-7.79 (m, 3H), 7.62-7.50 (m, 2H), 7.06 (d, J = 5.3 Hz,1H), 6.92 (s, 1H), 5.46- 5.30 (m, 1H), 4.48 (br s, 1H), 4.37- 4.18 (m,1H), 3.92 (s, 3H), 3.44 (br d, J = 13.3 Hz, 1H), 3.31-3.11 (m, 2H), 3.05(br dd, J = 6.5, 13.6 Hz, 1H), 1.56-1.33 (m, 18H). 141(S)-5-(tert-butyl)-N-(7- (2-((1-methyl-1H- pyrazol-4-yl)amino)pyrimidin-4- yl)-3-(oxetan-3-yl)- 2,3,4,5-tetrahydro-1H-benzo[d]azepin-1-yl)- 1,3,4-oxadiazole-2- carboxamide

LCMS: Rt 0.87 min, m/z 544.3. ¹H NMR (400 MHz, METHANOL-d4) δ: 8.39 (d,J = 5.02 Hz, 1H), 7.85- 8.03 (m, 3H), 7.64 (s, 1H), 7.51 (d, J = 8.03Hz, 1H), 7.18 (d, J = 5.27 Hz, 1H), 5.26 (d, J = 6.78 Hz, 1H), 4.72 (d,J = 7.28 Hz, 4H), 3.89 (s, 3H), 3.79 (d, J = 6.27 Hz, 1H), 2.21-3.29 (m,6H), 1.47 (s, 9H). 142 5-(tert-butyl)-N- (7-(2-((1- methyl-1H-pyrazol-4-yl)amino)pyrimidin-4- yl)-3-(2,2,2- trifluoroethyl)-2,3,4,5-tetrahydro-1H- benzo[d]azepin-1-yl)- 1,3,4-oxadiazole-2- carboxamide

ESI-MS (M + H)⁺: 570.3. ¹H NMR (400 MHz, CD₃OD) δ: 8.29 (d, J = 5.2 Hz,1H), 7.85-7.79 (m, 3H), 7.52 (s, 1H), 7.41 (d, J = 8.0 Hz, 1H), 7.08 (d,J = 5.2 Hz, 1H), 5.14-5.13 (m, 1H), 3.78 (s, 3H), 3.36-3.23 (m, 3H),3.15-3.09 (m, 2H), 3.01-2.92 (m, 2H), 2.86-2.81 (m, 1H), 1.35 (s, 9H).143 5-(tert-butyl)-N-(3-((S)- 2-hydroxypropyl)-7-(2-((1-methyl-1H-pyrazol-4- yl)amino)pyrimidin-4- yl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-1-yl)- 1,3,4-oxadiazole-2- carboxamide

ESI-MS (M + H)⁺: 546.3. ¹H NMR (400 MHz, CDCl₃) δ: 8.95-8.79 (m, 1H),8.41 (d, J = 5.2 Hz, 1H), 7.87- 7.78 (m, 3H), 7.56-7.54 (m, 2H), 7.04(d, J = 5.2 Hz, 1H), 6.97 (s, 1H), 5.18-5.14 (m, 1H), 3.92-3.91 (m, 1H),3.90 (s, 3H), 3.39-2.43 (m, 8H), 1.43 (s, 9H), 1.23-1.21 (m, 3H). 1445-(tert-butyl)-N-(3-((R)- 2-hydroxypropyl)-7-(2-((1-methyl-1H-pyrazol-4- yl)amino)pyrimidin-4- yl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-1-yl)- 1,3,4-oxadiazole-2- carboxamide

ESI-MS (M + H)⁺: 546.3. ¹H NMR (400 MHz, CD₃OD) δ: 8.40 (d, J = 4.8 Hz,1H), 7.97-7.90 (m, 3H), 7.64 (s, 1H), 7.51 (d, J = 8.0, 2.0 Hz, 1H),7.20-7.18 (m, 1H), 5.26-5.24 (m, 1H), 4.01-3.98 (m, 1H), 3.90 (s, 3H),3.27-3.21 (m, 2H), 3.14-3.03 (m, 2H), 2.85-2.80 (m, 1H), 2.70-2.56 (m,3H), 1.46 (s, 9H), 1.26-1.23 (m, 3H). 145 5-(tert-butyl)-N-(7-(2-((1-methyl-1H-pyrazol-4- yl)amino)pyrimidin-4- yl)-3-(tetrahydro-2H-pyran-4-yl)-2,3,4,5- tetrahydro-1H- benzo[d]azepin-1-yl)-1,3,4-oxadiazole-2- carboxamide

ESI-MS (M + H)⁺: 572.3. ¹H NMR (400 MHz, CDCl₃) δ: 9.02 (d, J = 7.2 Hz,1H), 8.41 (d, J = 5.2 Hz, 1H), 7.87 (s, 1H), 7.81 (dd, J = 8.0, 1.6 Hz,1H), 7.76 (d, J = 1.6 Hz, 1H), 7.58 (d, J = 8.0 Hz, 1H), 7.53 (s, 1H),7.03 (d, J = 5.2 Hz, 1H), 6.98 (s, 1H), 5.11-5.08 (m, 1H), 4.05-4.02 (m,2H), 3.91 (s, 3H), 3.41-3.25 (m, 5H), 2.92-2.67 (m, 4H), 1.76-1.63 (m,4H), 1.42 (s, 9H). 146 5-(tert-butyl)-N-(3-(3- hydroxypropyl)-7-(2-((1-methyl-1H-pyrazol-4- yl)amino)pyrimidin-4- yl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-1-yl)- 1,3,4-oxadiazole-2- carboxamide

ESI-MS (M + H)⁺: 545.7. ¹H NMR (400 MHz, CDCl₃) δ: 9.02 (d, J = 6.8 Hz,1H), 8.40 (d, J = 5.2 Hz, 1H), 7.89-7.76 (m, 3H), 7.57-7.52 (m, 3H),7.03 (d, J = 5.2 Hz, 1H), 5.13- 5.10 (m, 1H), 3.94-3.84 (m, 5H),3.32-3.15 (m, 3H), 2.90-2.67 (m, 5H), 2.45-2.42 (m, 1H), 1.83-1.81 (m,2H), 1.43 (s, 9H). 147 5-(3,3- difluorocyclobutyl)-N-(2-methyl-8-(2-((1-methyl- 1H-pyrazol-4- yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro- 1H-benzo[c]azepin-5-yl)- 1,3,4-oxadiazole-2-carboxamide

ESI-MS (M + H)⁺: 536.2. ¹H NMR (400 MHz, CDCl₃) δ: 8.43-8.42 (m, 2H),7.87 (s, 1H), 7.85-7.82 (m, 2H), 7.55 (s, 1H), 7.46 (d, J = 8.0 Hz, 1H),7.05 (d, J = 5.2 Hz, 1H), 6.94 (s, 1H), 5.60-5.56 (m, 1H), 3.98-3.88 (m,5H), 3.69-3.61 (m, 1H), 3.13- 3.05 (m, 5H), 2.87-2.81 (m, 1H), 2.52 (s,3H), 2.36-2.28 (m, 1H), 2.10-2.03 (m, 1H). 148 5-(3,3-difluorocyclobutyl)- N-(2- (2-hydroxyethyl)-8-(2- ((1-methyl-1H-pyrazol-4- yl)amino)pyrimidin-4- yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)- 1,3,4-oxadiazole-2- carboxamide

ESI-MS (M + H)⁺: 566.2. ¹H NMR (400 MHz, CDCl₃) δ: 8.88 (br, 1H), 8.42(d, J = 5.2 Hz, 1H), 7.85 (s, 1H), 7.84-7.81 (m, 2H), 7.54 (s, 1H), 7.47(d, J = 8.0 Hz, 1H), 7.05-7.02 (m, 2H), 5.61-5.57 (m, 1H), 4.12- 4.03(m, 2H), 3.91 (s, 3H), 3.81-3.60 (m, 3H), 3.38-3.04 (m, 6H), 2.95- 2.78(m, 3H), 2.39-2.31 (m, 1H), 2.12-2.05 (m, 1H). 149(R)-5-(tert-butyl)-N-(8- (2-((5,6-dihydro-4H- pyrrolo[1,2-b]pyrazol-3-yl)amino)pyrimidin-4- yl)-2-(2-hydroxyethyl)- 2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)- 1,2,4-oxadiazole-3- carboxamide

ESI-MS (M + H)⁺: 558.2. ¹H NMR (400 MHz, CD₃OD) δ: 8.35 (d, J = 5.2 Hz,1H), 7.99-7.97 (m, 2H), 7.69 (s, 1H), 7.42 (d, J = 8.0 Hz, 1H), 7.21 (d,J = 5.2 Hz, 1H), 5.59-5.55 (m, 1H), 4.16-4.10 (m, 4H), 3.74 (t, J = 6.0Hz, 2H), 3.27-3.13 (m, 2H), 2.96 (t, J = 7.2 Hz, 2H), 2.67-2.62 (m, 4H),2.33-2.24 (m, 1H), 2.00- 1.96 (m, 1H), 1.52 (s, 9H). 1505-(tert-butyl)-N-(8- hydroxy-2-(2-((1-methyl- 1H-pyrazol-4-yl)amino)pyrimidin-4- yl)-6,7,8,9-tetrahydro- 5H-benzo[7]annulen-5-yl)-1,3,4-oxadiazole-2- carboxamide

ESI-MS (M + H)⁺: 503.2. ¹H NMR (400 MHz, CDCl₃) δ: 8.74 (d, J = 4.8 Hz,1H), 7.88-7.85 (m, 3H), 7.76- 7.59 (m, 1H), 7.54 (s, 1H), 7.39-7.37 (m,1H), 7.05-7.03 (m, 2H), 5.41- 5.37 (m, 1H), 4.14-4.09 (m, 1H), 3.91 (s,3H), 3.89-3.84 (m, 1H), 3.26-3.19 (m, 2H), 2.24-1.96 (m, 4H), 1.49-1.44(m, 9H). 151 (R)-5-(tert-butyl)-N-(2- (2-((1,5-dimethyl-1H- pyrazol-4-yl)amino)pyrimidin-4- yl)-6,7,8,9-tetrahydro- 5H-benzo[7]annulen-5-yl)-1,2,4-oxadiazole-3- carboxamide

ESI-MS (M + H)⁺: 501.3. ¹H NMR (400 MHz, CD₃OD) δ: 8.31 (d, J = 5.2 Hz,1H), 7.93-7.91 (m, 2H), 7.60 (s, 1H), 7.38 (d, J = 8.0 Hz, 1H), 7.23 (d,J = 5.2 Hz, 1H), 5.44 (d, J = 10.0 Hz, 1H), 3.82 (s, 3H), 3.10-2.97 (m,2H), 2.25 (s, 3H), 2.09-1.86 (m, 5H), 1.54 (s, 9H), 1.49-1.43 (m, 1H).152 (R)-5-(tert-butyl)-N-(2- (2-((5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3- yl)amino)pyrimidin-4- yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5- yl)-1,2,4-oxadiazole-3- carboxamide

ESI-MS (M + H)⁺: 513.3. ¹H NMR (500 MHz, DMSO-d₆) δ: 9.57 (d, J = 7.94Hz, 1H), 9.06 (s, 1H), 8.40 (d, J = 5.49 Hz, 1H), 7.93-7.84 (m, 2H),7.62 (br s, 1H), 7.32 (d, J = 7.94 Hz, 1H), 7.21 (d, J = 4.88 Hz, 1H),5.26 (t, J = 8.85 Hz, 1H), 4.05 (t, J = 7.33 Hz, 2H), 3.17 (s, 4H),2.97- 2.91 (m, 2H), 2.91-2.83 (m, 2H), 2.54-2.51 (m, 2H), 1.99-1.89 (m,3H), 1.88-1.68 (m, 2H), 1.46 (s, 9H), 1.36-1.26 (m, 1H). 153(R)-5-(tert-butyl)-N-(2- (2-((1-methyl-5- (trifluoromethyl)-1H-pyrazol-4- yl)amino)pyrimidin-4- yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5- yl)-1,2,4-oxadiazole-3- carboxamide

ESI-MS (M + H)⁺: 555.3. ¹H NMR (500 MHz, DMSO-d₆) δ: 9.56 (d, J = 8.55Hz, 1H), 8.93 (s, 1H), 8.43 (d, J = 5.49 Hz, 1H), 7.89 (s, 1H), 7.86(dd, J = 8.2, 1.5 Hz, 1H), 7.79 (s, 1H), 7.37-7.28 (m, 2H), 5.25 (br t,J = 8.85 Hz, 1H), 3.95 (s, 3 H), 2.99- 2.86 (m, 2H), 1.99-1.88 (m, 3H),1.86-1.71 (m, 2H), 1.46 (s, 9H), 1.35-1.25 (m, 1H). 154(R)-1-(tert-butyl)-N-(2- (2-((1-methyl-1H- pyrazol-4-yl)amino)pyridin-4-yl)- 6,7,8,9-tetrahydro-5H- benzo[7]annulen-5-yl)-1H-1,2,3-triazole-4- carboxamide

ESI-MS (M + H)⁺: 485.3. ¹H NMR (400 MHz, CDCl₃) δ: 8.17-8.15 (m, 1H),7.66 (d, J = 8.4 Hz, 1H), 7.61 (s, 1H), 7.47 (s, 1H), 7.37-7.30 (m, 3H),6.87-6.86 (m, 1H), 6.70 (s, 1H), 6.13-6.09 (m, 1H), 5.41-5.38 (m, 1H),3.91 (s, 3H), 3.03-2.92 (m, 2H), 2.03-1.93 (m, 4H), 1.87-1.84 (m, 1H),1.71 (s, 9H), 1.63-1.55 (m, 1H). *indicates that the stereochemistry atthe chiral center is arbitrarily assigned. **indicates that the relativestereochemistry at the two chiral centers for the racemic mixture isarbitrarily assigned, i.e., the trans- or cis-configuration at onechiral center relative to the other chiral center is arbitrarilyassigned.

Example 155. In Vitro BTK Kinase Assay: BTK-POLYGAT-LS ASSAY

The purpose of the BTK in vitro assay is to determine compound potencyagainst BTK through the measurement of IC₅₀. Compound inhibition ismeasured after monitoring the amount of phosphorylation of afluorescein-labeled polyGAT peptide (Invitrogen PV3611) in the presenceof active BTK enzyme (Upstate 14-552), ATP, and inhibitor. The BTKkinase reaction was done in a black 96 well plate (costar 3694). For atypical assay, a 24 μL aliquot of a ATP/peptide master mix (finalconcentration; ATP 10 μM, polyGAT 100 nM) in kinase buffer (10 mMTris-HCl pH 7.5, 10 mM MgCl2, 200 μM Na₃PO₄, 5 mM DTT, 0.01% TritonX-100, and 0.2 mg/ml casein) is added to each well. Next, 1 pL of a4-fold, 40× compound titration in 100% DMSO solvent is added, followedby adding 15 uL of BTK enzyme mix in 1× kinase buffer (with a finalconcentration of 0.25 nM). The assay is incubated for 30 minutes beforebeing stopped with 28 pL of a 50 mM EDTA solution. Aliquots (5 uL) ofthe kinase reaction are transferred to a low volume white 384 well plate(Corning 3674), and 5 pL of a 2× detection buffer (Invitrogen PV3574,with 4 nM Tb-PY20 antibody, Invitrogen PV3552) is added. The plate iscovered and incubated for 45 minutes at room temperature. Time resolvedfluorescence (TRF) on Molecular Devices M5 (332 nm excitation; 488 nmemission; 518 nm fluorescein emission) is measured. IC₅₀ values arecalculated using a four parameter fit with 100% enzyme activitydetermined from the DMSO control and 0% activity from the EDTA control.

Table 1 shows the activity of selected compounds of this invention inthe in vitro Btk kinase assay, wherein each compound number correspondsto the compound numbering set forth in Examples 1-154 herein. “†”represents an IC₅₀ of equal to or less than 1000 nM and greater than 10nM; “††” represents an IC₅₀ of equal to or less than 10 nM and greaterthan 1 nM; and “†††” represents an IC₅₀ of equal to or less than 1 nM.

TABLE 1 IC₅₀ (nM) Compound No. ††† 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11,12, 13, 14a, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24a, 25, 26a, 26b, 27,28, 29, 30, 31, 32, 33, 34, 35, 36a, 37, 38, 39, 40, 41, 42a, 44, 54,55, 58, 59, 68, 70, 71, 72, 73, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84,86, 87, 88, 89a, 90, 91, 92, 93, 96, 97, 98, 99, 101, 102, 105, 106,107, 111, 112, 114, 117, 119a, 116, 121, 122, 124, 125, 127, 135, 149,150, 152, 153, †† 43, 45, 46, 47, 49, 48, 50, 51, 52, 53, 56, 57, 60,61, 62, 63, 64, 65, 66, 67, 69, 74, 94, 95, 100, 103, 110, 113, 115,123, 126, 128, 129, 130, 131, † 14b, 24b, 36b, 85, 89b, 108, 109, 132,133, 134, 136, 137, 138, 139, 141

Example 156. In Vitro PD Assay in Human Whole Blood

Human heparinized venous blood was purchased from Bioreclamation, Inc.or SeraCare Life Sciences and shipped overnight. Whole blood wasaliquoted into 96-well plate and “spiked” with serial dilutions of testcompound in DMSO or with DMSO without drug. The final concentration ofDMSO in all wells was 0.1%. The plate was incubated at 37° C. for 30min. Lysis buffer containing protease and phosphatase inhibitors wasadded to the drug-containing samples and one of the DMSO-only samples(+PPi, high control), while lysis buffer containing protease inhibitorswas added to the other DMSO-only samples (−PPi, low control). All of thelysed whole blood samples were subjected to the total BTK capture andphosphotyrosine detection method described in US20160311802,incorporated herein by reference. ECL values were graphed in Prism and abest-fit curve with restrictions on the maximum and minimum defined bythe +PPi high and −PPi low controls was used to estimate the testcompound concentration that results in 50% inhibition of ECL signal byinterpolation.

Table 2 shows the activity of selected compounds of this invention inthe pBTK assay, wherein each compound number corresponds to the compoundnumbering set forth in Examples 1-154 described herein. “†” representsan IC₅₀ of equal to or less than 10,000 nM but greater than 500 nM, “††”represents an IC₅₀ of equal to or less than 500 nM but greater than 100nM; and “†††” represents an IC₅₀ of equal to or less than 100 nM.

TABLE 2 IC₅₀ (nM) Compound No. ††† 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12,13, 14a, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24a, 25, 26a, 26b, 27, 28,29, 30, 31, 32, 33, 34, 35, 36a, 37, 39, 40, 41, 42a, 44, 56, 58, 60,62, 63, 64, 65, 67, 68, 71, 72, 73, 75, 76, 77, 78, 79, 80, 81, 82, 83,84, 86, 87, 88, 89a, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101,104, 105, 106, 107, 110, 111, 112, 113, 114, 119a, 120, 121, 122, 123,124, 125, 126, 152, †† 38, 42b, 45, 46, 47, 48, 49, 51, 52, 53, 57, 59,61, 66, 69, 70, 74, 102, 103, 115, 117, 118a, 118b, 127, 128, 129, 130,131, 132 † 14b, 24b, 36b, 43, 50, 85, 89b, 108, 109, 116, 133, 134, 135,136, 137, 138, 139, 140, 141, 153,

What is claimed is:
 1. A compound represented by the following formula:

or a pharmaceutically acceptable salt thereof.
 2. A pharmaceuticalcomposition comprising a compound of claim 1, or a pharmaceuticallyacceptable salt thereof, and a pharmaceutically acceptable excipient. 3.A compound represented by the following formula:

or a pharmaceutically acceptable salt thereof.
 4. A pharmaceuticalcomposition comprising a compound of claim 3, or a pharmaceuticallyacceptable salt thereof, and a pharmaceutically acceptable excipient. 5.Crystalline Form A of(R)-1-(tert-butyl)-N-(8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(oxetan-3-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1H-1,2,3-triazole-4-carboxamiderepresented by the following formula:


6. A pharmaceutical composition comprising a crystalline Form A of claim5 and a pharmaceutically acceptable excipient.
 7. Crystalline Form G of(R)-1-(tert-butyl)-N-(8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(oxetan-3-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1H-1,2,3-triazole-4-carboxamiderepresented by the following formula:


8. A pharmaceutical composition comprising a crystalline Form G of claim7 and a pharmaceutically acceptable excipient.